Council for Tobacco Research
Chemical Carcinogenesis in Syrian Hamsters: A Review (Through 1976) Progress in Experimental Tumor Research, Vol. 23 [St Hamsters Are Useful Experimental Animals for A Variety of Carcinogenesis Studies]
Fields
- Master ID
- Ctrmn00041967-2810
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- Author
- Progress, I.N. Experimental Tumor Research
- Homburger, F., Bioresearch Inst
- Depository Date
- 08 Sep 1997
- Box
- 267
- Type
- SCIENTIFIC ARTICLE
- UCSF Legacy ID
- jot30a00
Document Images
/1
Prog. ap. Twnor Ret., wl. 23, pp 100-179 (Karisr,laal 1979)
Chemical Carcinogenesis in Syrian Hamsters :
A Review' (through 1976).
F. HowruROER
8io-Rtrsardt Instituta. CambrWes. Man.
COR1Cnll
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
I l. Sk in . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
111. SrEevunwut Tiuur . . . . . . . . . . . . . . . . . . . . . . . . . 10d
IV. CJt.ek Poucit . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
A. MstAods. . . . . . . . . . . . . . . . . . . . . . . . . . 107
III. HiuocHattistry, Fim Strvt:utr., Cytolov . ... . . . . . . . . . . . . 110
C. Modifyins Factors . . . . . . . . . . . . . . . . . . . . . . . . 1 f t
V. Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
V I. Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 f
VIi. Retpiratory Tract . . . . . . . . . . . . . . . . . . . . . . . . I I t
Tracheal Instillation ot Cercirtowie Asenta . . . . . . . . . . . . . . . 12!
VIII. inhatation ... . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
IX. Gaurointatinal Tract . . . . . . . . . . . . . . . . . . . . 146
X. Livc+ and Diliary Trttet . . . . . . . . . . . . . . . . . . . . . . . . 151
Xi. Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
XII. Urinary lladda . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Xl l l. hatute . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I ha
XIV. Ovary and Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . 10
XV. Taticla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
XVI. Mamnury Gland. P.ncreae. Adtenal . . . . . . . . . . . . . . . . . . 166
Raferentxs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
I TAis work .as supponed by USPHS General RaearcA Supc+on GrnRt SOtRt:.
03523 ( Cir.i.uon of ReuarsA Raourea and Faalitia). Raeard+ Suppoct Gr.nu CA 1 J Zll
and CA-1f/23 (National Cancer Instituul, and by Rio.Raearcb Coruulunu. Ine
Cy~ R t 1i f 7 '4..+* 4.G. 67'
a 1
CAcmiesl Carcinofenais in Syrian Hanatert 101
l. Introduerion
Hamsters continue to be important in experimental arcinopnesis
studies. Their check pouch remains a unique and most usetul tool. In some
emerjinr areas, their use is becoming especially fruitful. Such 6elds include
studies on renal ancers, induction of neoplasms and preneoplastic chanps
in the rapiratory tract by direct application of particulate carcinogens or by
smoke inhalation and urinary bladder araooIIeoais. It also bejins to appear
as if hamsters will become useful models for gastrointestinal arsiaosenesis
and for studies with inbred h.imstera, which once more make clear the basic
truths much earlier realized in mice, of genetic control of anoer suseepdbility
or mistance. Not only does every species possess its own pattern of mponse
to various arcinogens, but, within species, inbred lines diAa markedly in
their susceptibility to carcinogens. Sex is the only equally striking modi6er
of arciao=enesis. This genetic control of cancer susceptibility pertains not
only to diJfaent chemical carcinogens, but also to viral cancers (102, 193J.
Reslirstion of this fact renders it most important that the susceptibility or
resistana to carcinogens of inbred lines of Syrian hamsters be arefupy
studied and deSned, so that only susceptible lines wiU be used for screening
of substances for carcinogenic activity. The genedally determined diAereaoes
of carcinogen susceptibility also provide a tool tor the study of inethaaisms
of cancer production.
It is of jrat importance for the comparative study of various rsports
in the literature that the hsnutera used be clearly identilted in terms of their
source and genetic constitution. This is not always done at present, ta that
much published work, especially that done with sandombred animals, is
ditTicult to interpret and the results may not be reproducible.
The l;terature on chemical aranoteaesis in the Syrian golden hamster
was first reviewed in 1968 and 19ti9, and updated (tluouilh 1971) in 1972
(74, 75, 77). The Gterature sina then has betn monitored in part through the
use of DIOSIS, a computer-based information servia on the journals covered
by Biological Abstracts. Thers an now sulficient new data in the most recent
literature to warrant a further review to update the previous ones.
As in the first papers, the writing technique suggested by SiLYt wi11 be
used: The reviewer's summaries and evaluations of published material ars
printed in standard type, while the abstraets, mostly taken from published
papers, are grouped and printed in petit type.
To facilitate the cross-referencinS of this review with earlier ones, the
original order of main hcadings will be used. Throughout this review, the
~~`mR IMIN 042675
a 1
Ha+avsca 102
abbrsviations in the extnrae left column of the folloMinj list of chemical
arcioojens will be used. ~
A (I): Ilauf8)aethraesne
>f! (2): Sam*
(1): ba+ao(.)vyRM
DDC (2): Sam.
(1): 7HDib.are (a,r) arl+asoit
DBNA (2): Sanr
(1): NNiverodibuty4ntint
DENA (2): NIIWyl,/weitro.olbusaeaadn.
(1): N-Nivesodiethylamin.
DMDA (2): NEthy{.N-nivasaaAanunine
(t): 7,12Dimahylbeatl.kntMaases
(2): tamt
DMSO (1): Dimethyl wllosids (pnlmed) ot mtUhyl Wafoiide (altsto~tt)
(2): tutfmyteis(m."e.)
MC (1): 3-MahytdaiaetAnew
a: )yDibydrs)anahyfbensl i}MstMybn.
NMU (q: 1MahyllWAoWvrq '
v a):
a): MMe1AyLN~aitraouns
Wyl ~
NNHMI rn:
(1): Sam
Haahydre+aia~d N4s
epift
(2): Sanr
NM (I): 4-NivaamoPholim
(2): Ikm
NN.v
Nt (a:
rn:
(1): 1Duty4l-aitrnaaan
NDuryl.N-mvaau..
tNivaopioaiditr
(2): Sanr
DMN (1): NNivewOimeNylamine
(2): A~Mahy4Meivaometa.auaias
DPPt (1): NNitraodiyropyhn+ias
(2): NNitraoN-qropyFt ~rop ~eartiia~
MTN (1): NMahyLNrtivaop~Dpyl .nwr
(2): NMaAyi~Ntivaal -prop aaamias
V' I b R / l N 042M M' . 6
.
C
a
Chemful Gre;nopenais in Syrian Hanum
D!N Dupliaa of DDNA, abore
2HPPN (I): 1{hopylnitrosantino}2-propanot
(2): 1{Nivosoyropyla mino}2-propanol
DHPN (1): 1,1'{Nitrosimioo)di-2-propanol
(2): 1,1'{Nitroainaino)bis(2-propanol)
DMDPM (1); 2,YDimeNyl.)V-eitror:octipropylamine
(2): 2-MaAyI-N{2.a+aAylpropyl}N-nitrao-l-txooaaamier
/k
103
(1) Narna,ocordiep to the rvMr of oTpr+ie eontenelaure of the Istt,reatio/al Uoioa
of Pure and Applied CTKmiutry (IUPAt7; alr.o G4mie.l AlrrF,reu aamr for the
!xeriws (19t:7-: ^ 1) iods+t period.
a) Caaeia/Abser.ar, nanr ror tha erareat (t972-1976) indes pariod.
Tse author paufully acknowbd{es the kind o8ioa of Dr. Kuar L Loomro,
Die.ecor of Noma+clature, t3ea+ical Abstracts 9erviot, The OBio State Ueivasity,
Cotumbus, Ohio, in trompilina this list.
11. Skin
While La et al. (101] had previously reported melanotic skin tumors
with a single subcutaneous (s.c.) injection of DMBA to aewbora haansters,
Auaatf er al. (10,11] observed similar tumors after single iotratastric(i.6.)
doses of DMBA (20 rnS(100 6 body wei jht) given to male or femak haautea
ajed trom 6 to S weeks. They observed a significant incnase in the oumber
(but not size) of tumors following pinealestomy. This effect of ablative
pineal surgery wu more marked in males than in females.
ln our own studies involving s.eL and i.g. administration of DMBA,
we have never seen mdanotie skita tumors. The description of AuttatT's
melanotic tumor so closely resembles that of GtUm er al. (1. oata. Caaar
Inst. 40: E67-t77, 19681 that we are tempted to spexv4tt tAat pottsibly the
hamsters used by AuntxT's group earried the GmlG vinu, wbich atay have
been activated by DMBA. (Glum: ?umors arose by proliferatioa of hair
follicle cells, usually those of the ha.ir route epithelium...'; Auaur: These
melanocyta proliterate intensely in the derma which etuJoses the hair fol
L'cles, at the expense of which these tumors appear to be born' (reviewer's
translatioop. AeocptinS this assumpdon, we would then postulate that no
such skio rumors are induced in B10 strains because they may be free of
Gral6's virus.
0
0
PT
C T R I I N 0 4 2- 6 7','r'q
HnrtVROa 104
At»[RT H.l. (I0): FortyeiBht hous after pineileetomy (or eh.im operatioa. or no
trntment). Syrisn aolden hamstcrs (I1-43 eRotti-4 animals per Broup reponed) reeeivb
a sinpk dots (by gastric int6bation) of DA!!A in 'Labrafil 19a0 GS'. 7.5 ma/100 e body
treatht. Sacri(ioe was made 13 months a(ut thk trcstment. Melanotic tumors apttand
as early as a months sthor treatment and varied fran I mm in diameter to 2-3 em in
diameter. The authors eondude: (1)'fhe adminiseration af.a single dose of DAtBA bs
stomach tube indxa Ain mds>,otie tumor>i ofthin 4 atonthe i>t n+ale and in femalt
hamsters. (2) Pinesbetomy :eaaato ooeuidecspy tAe aumber ot the thae tumors, but,
pinolatomftatd famaks produce kwer melanaie tumorta {hsa tnales. (3) linealsctoe7
sRaeu neid+er sist nor histological appearartee of thee tun+ors.
AuaRt sr of. ( I 1): SinSle doies o(DM LA in LabraRl (1l44 CS) ~rers Biven to male
and female Syrian Bctdea hanuur>t at 6-i weskt<of ape. The dow varied from a to 33.3 mS/
100 B(wdy usight, but dosea above 20 mB.r100 g e.r. were found to be toaic. The animals
wsre ssaifieed Ll3 momha beyond thia treatment. 1Khile aintilat utatrtKns with 8A failed
to produae mdanoue tumoea and no eueG tumora aert e.ea in 37 hamsters or both t;aes,
all DMBA1rn+ed aninub had nrctanotie tumon. The bum finr (3.t.months) and the
number of nrianot+: t.mon were proportional to the do.e and a function of the length
of the observation periid. l.4ost of thaa ttamors wsre unsll (below 1 mm dianwer). s few
were larp (r.erd oa+umeurt); they were Iraniptantabk growb+i alowly and never
metastasuins Aleer reketion of tueh tesnsplantabb traroors, thees veas no rsatrrsnw.
Thers .ere so tra tWTerenm A fsr aintilary v..ud p.nitlly a)biso' huenteas (sero.
tnclanio .Nts') .W dnelno.d ntdanotle ttanoras. Other tunaa observed in hamsters
fotlowin{ sin{b do.M d D M BA were se6.oaota eyas, erib of th. o.ariea. iplcnie taiorr,
adrenal tumon. pwe epiUtdianae aud eta+atatr sdeAOaroeoetas~ HietoloBiaUy, the
enelsnNie tumen wi dewribsd rs benipt.
Lu sr.t. "01(: T1w paper re0oro *ert tba to 1at tbe alf.etirer+as of DMBA
when Biva+ ia a uork inpetion to the trwboett bsa>st.v. rat and e+ouu. Careinoyen was
sdminister.d in v.N-opr7lin (Trioetanois) trom Eastman OrpAic CAentinb. Nw York,
N.Y. The ttot+c>nstrauar ef DMBA ware weA tAst the artaunt of wlvent was 0.03 ml.
Daes of 1.000. 200 and 100 vi produced subaLneoul sueomas and detmsl e+dano-
tytomst. Add;tionapy. a slight aooderaAon of the apporana of maliBnuu lymchoma
.vat founJ. In comr.-.b in Ut. Swiss and AKR txrainr+ of mia, then wen tumon distant
from the applia.toe sita namdtr. fMepitansa and hatB adonomttr la the case of Lewis
nn, there were asenually local ranaro. T!r mioraas and ebs e+elsnocytonus iodueed
by Qw praeedure were sion;lar ia appearanw and ntivnaoopr to thoee induced in adu)t
harrote>s.
111. 3"6curaKaw Tduus
Sueomas of tbe subcutaneoua tissue have been induced in Syrian
hamsters with MC, 8P, Nnitrosobutylurea (neurosarcomas), DMBA and
atetals, and the pro.M c)vyacteristia of induced tumors in transplanu and
tissue cultures as wrll as thrr ebromosornai properties have been studied.
Various nickel a+e+pounds and titanocsae dichloride vwert found to be ar-
~'°''~~~ 042~ -~ ` S
CTR
/1
,
1
Chemical Careinopena's in Syrian Hamatcrt tOS
dnojenie. Sarcomas induced by BP in the mature oRsprinj of hamsters
injected s.c. on the second day of pregnancy with Freund's incomplete
adjuvant appeared earlier and frew more rapidly than did similarly induced
tumors in the offspring of uatreated mothers.
DIP.oto rt.l. 127): Sia primary subcutaneous tumorz induoW aith a single inj.pion
of at' or DMBA were analr:ed for hiuopstholow, growth in rirro, tnnsptanubiliq, and
karyokKy. All tumon usn bbraueomat with varyint degrees of diRaauiation. Tunrot
wltueas wae ehuansrited by rapid growth and inarpfs in acidity of m.diuen fotb..d
by quick dsperwatioo and wrvival ot a fow a1b which produoed a population that gw
indtelinftdy in Nrnt. Thr initial populations wen diptoid. twr diploid, or taraploid aed
Aad some aantrie pieess, chromatic rteananacmonu, and nsarts ehroerowm. hut
aithout any eemmon karyotypic cAanae. Subaet{uentlY. Aeteroploidy incotaaed. Ctitt
Leked orioetatioo and oorasionally piled up. CGoninp without a l.edv taW- a+d is dinraa
adoniee, some of which were randomly orieaued with eriaerotsinp of R4ntents. Tunton
derFvtd from tbeu wlturn
.at trampiaenblt iato I+anwen Ttwe prnors .w mor. .
anaptastie than primary tumors. Cempariaon of thae studies with iu.1mn studies in which
quantitative tramtorn>,tion was obtained with Syrian hsmstp tnnhryo edb and polyeyeli0
hrdroarbon carcinogens hads to the oa+dution that is.rtn inveatiptions of tramlotttr.
tioe pro.ida information rekvant to In d.o tranuorntatbn. (Authon' atxuact.)
Ftmsr and ScMUuoa (441: Groupa of random-bred hansten or t>oJt wea wsighini
l0-73 a were given monthly inttumasvlsr h+janioro of nieksl po.der, ttictdaeset or
titanasne auspa+dsd in trioctanoin. Tramptantable dbroareoenas .en induced in a low
ptxcsnup of the aaimab that received nietd po.der or nictdooane. la oontraa, higher
twwr ineidcnoet wers observed in FocAer-3N nts. Genvatiutipts drawn (roat a tom-
patisoo of inbred rats with random-bred hamuen ans probably not valid. lnbnd ardao.
een-wseeptibk lina of hamuen ought to be studied.
HorwaoU a.1. (79): Single s.t: injsetioer Mt triraptrlia of 300 µa or Ait^ or Dp
or DMBA produced aa sareoma at the injectiat tit+ of aeou rou.d inbeed aralna of
Syrian hamsters. DA produced so tumon at t!r injaetien aitet Iw.e.+r, io twe inbnd line
(S10 t7.2o) 10% of the trnted fatuM developed broeehiotar adenomuom.
The nte of tumor dcveJopnwtt and ths twraber of twnen .an.d depending oa tJ>e
inbred linez For all of the taud arsinopens, the same theee inbred t"ina were teora
auaoeptibk than mou of the other finea teated (B101c7-210 310 i3.3, 210 1S.1i). Fwdint
of MC awed ardnoeus of the purointestinal trael, fsmale rsproduaiva USM aad
mammary {Iand is sia inbred tuw and ons randomly bred tine o( Syrian hantnera. Whaea
in thM randomir bred tins the newltt wn aiawtu te those rsponed t+rerviowsly by aUA
Po.rt. the incidsnes of a{t wtnoes varied widely amon{ inbred sulifr, tlt" rnv.rlina
dut penetie factors eovern the responses ol Sy+i+o paatems to arcrwecnesis by patrie
intubation of MG Geneties appcu to determine the napaui.enes or epvsppui.enaa
in penerat of inbred Syrian hamsters to carcinogenic stimuli. Knowledge of thos rh.it.d
.arubls susceptibilities makes potsibtt tbe ntionaJ ntactioe of inbnd ti.ef that ate hat
suiud for artain atperiments. (AutLara' aEatraet.)
(A.nwa.u and Surirct (1111: NNittoso0utrturn iejacted aelly is. in 1% ethyl
akohol a a doae ot20 wNt body weiaht, beginning in 7.day-old hsmuert, eautsd 12 aanp.
tarsomai in 21 surviving animals so treated. Nona of these twnon, which oacvned at
the inj.ction siu, rnembkd the hunun m7zoid type of neuroacnie saroono,
CTR f f f 7 0426Yi 9
i
W
/1
106
Popest:V and GXoe. 1l)aj: tumour pdYRssafe driputer a tnroplant{tion
method trsed on the repeated and xheduMd interruption of tumor graft with the purposa
of in8uendng the develepment e( trophic phenomena and the relations bxtwesn tumor
implant and host. hrimary tumee>s induad by )-nethykholanthra+e in polden hamster
-e cyto{snetiaatly atWyaad after monotoie monoatrie oolypruie (6 times ia at t,
intea^.b).
CAromaontal constitution af tM tumow which did t+et underso poty9assap was
seersploid. Follonrin= the polhpastap of tbe pdmuy tueow in anogenek taolden hamste
of oppaia as, twr diploid and nornal diploid cells of the boN wat pndominant. T'he
significance of thia nadihation is disatm.d u related to the Inuewne reettonse of the host
to the uadifl.d propenia of tAe tumor imtsfant by polypawae. (Authon' apstraet.)
IV. Cbeek PateA
Studies on the eheek pouch may be divided into those dealing with
histology (including fine structure) and histochemistry of developing induced
neoplasms, and studies concerned witb modifying factors of.arcino=enesis
at the eheek pouch site, indudin= experiatental radiotherapy and chemo-
therapy (E2) of induced lesions as well as ae of the pouch for the testing of
suspected carcinogens (34, 193J. DMBA, the carcinopen of choice in these
studies, was ta:ually applied aa an 0.3% solution in puaQtn, aatone or
'Orakisse'. For weaker arcinotent, a technique was .uuested 'which en-
e:oses the test material into selatin capsules and polyethylene sheet for
:radual release and repeated replaoement 1151},
Fine structure studies reve:aled the formation of pt+eudopodia by trans-
fortnin= epithelial txlls which wete no IonSer d'Win=uishabte at the onset of
Nistolo=ially reeolnirabk cancer (1911~ NMU was also used topically and
introduced rhabdomyoblastornas in 32% of the treated animals, and sastric
tumor in 44% (1931
Studies on the early Gght tnicroscopic changes uen in DMBA arcino-
Senesis in the vascular elements of the cheek pouch show that neurovascular
changes in the terminal vessels do oeau extren+ely early (25,26). Studies on
the inflammatory response to DMBA showed a steep and steady rise of
maerophsM concomitant with tumor development (44 Some of the histo-
ehemical techniques for aryl hydrotylases trvcaled a particulate rnction -
produet in epithelial alit, and some of these partieles possessed properties
of lysosotnes. Changes in siss, ttaininS properties, number and fragility of
the lysosome-like and other ptuticles were observed in arcino=en-trated
epithelium before any histological or cytological evidence o[ premaliinancy
(172, 173). Changes found in human prernalipunt oral lesions resembled
4j TR I , I V' 42;sM 1+* -..d
4
t:Aanieal Csndnoeemis in Srrian Nanwe+s to7
those found in preancerous lesions of hamsters. During the course of ar-
cinoSenesis, marked increas.s in DNA content in basal and parabasal cells
were observed (14j and DMBA !Jnjutated DNA synthesis in an increasing
number of cells (192j.
In exfoliative cytology studies during arcinosenesis, typical cells were
found in the earliest erythematous lesions (40j. In the premalignant stau,
pseudopodia =rowin= into the intrsepithclial spaces were observed (1991
In malignant basal cells, the total length basal ttsembtsne was inasased
and the total lengths of desmosomes and hemidesmosomes were decreased;
this may be associated with greater cell mobility (t961.
Fine structure studies revealed the formation of'pseudopodi hy trat:s-
tor+ttia; epstl;eliat oslls which were no longer distinguishable at the onset
of histolojially recognizable cancer (19d). NMU was also used topically
and introduced rhabdomyoblastomas in 32% of the treated animals and
gastric tumor in 44";.
Modifying factors of arcinopnesis (or of established, induced tumors)
have been studied in the hamster cheek pouch. Such factors include chronic
irritation and trauma (170j, metals, speci6ally zinc (13E), castration (103j,
hormones, testosterone (132j, cortisone (13Sj, cortisone derivative in DMSO
(171j, vitamin A(132,133j, vitamin Ds and Da (fS7j, antilymphocyte urum
(46j, and bacillus Glmette-Gudrin (43j. Therapeutic a=ents, such as X-rnys
(t51, and chemotherapeutic agents (cyclophosphamide, metbotreute and
vinbtastine) have also been studied (106j. Chlorpromazine also was used to
suppress urcinojeneLis of DMBA when applied to the eheek poucb prior
to, or with, the arcinogen (103, 1341. Human saliva, on the other hand,
did not protect against DMBA arctinojtrtesis (1l9j. The effects observed
with various moditying factors are summarized in t,abk l.
A lesion described as'lyrnphotaalike' was induced by three times weekly
application for 12 weeks of vitamin A palmitate in liquid para/firt (20% w/v).
Theu appeared to be chronic inAammatory esudates rather than lymphomas
(104j.
A. Methods
Ramaeru. 1131) (w al.e pp. It!): A lachniqut i1 deaeribed for Mltina uepaeud
earttinoyrnio wbwnce in tAe twrota't cAxsk pouclt.lt awuiau in iftening into tM d+"k
poucha pani.llr Aeatlealed polrethrlens beg containing ta1 iubuance in multiple gelatin
eapsuks. It b espesuly witable for wnky careinoSenic tompounJr tlut nuy npuin: the
full Ws span of tAe u+snat bslon sfttusa elLnps. The nuut.dsnuea ars simplicity,
k
Lr t R i i N 0"T 2 f..A Si. JF .11
I- .
HoM.vacea
108
Ta6/e I. Modiflinp faaon of arano0setesh as uudi,:d ia tAe hamsw cheek poud,
with DMBAinduoid neoplatnu
1-_
Substanot studi.d Routs At what ape Efact obeerved Reterena
Ch'ron'r if. italia..
`I
tsrcinoGen
BivCR _ .
0:!% DMBA 7 per top;r d i momt.. .one
wek plus 3 nar
incision at 12 weeks or
Rtanipuladon of tissue
Zinc
0.5% DMBA 7 per p.o.
week for 1.eeks Zn In
tkinking water;
1001>0m in addition
to 21.9 ppm in dist
Hormones
Gstration 2.eeks topins
before appliotan of
03% DMBA ie
p.arsAin each week
for up to If ..eks
7stoeterone: nurs- LaL
lion of inuKt nuM
hannten, I wak
before^3SC CR1BA
sns applied 7 pa
e,.ek (9-12...eks);
! 3 n,e or tstosaron.
propicelay
'I.nL 2 K per.eek
Coniwne acesate: topie.l
DMI3A 0.3% in
osnRm I pw.esk;
oortisone 0.05%
applied sinwltarrously
for 12 weekt;
7riamt:inolone
Wlirors~I I d, Ifd 11
21resMrdroryvrep+.-
l.r-dierm 1.20 dionq
In DMSO 0.023'ii topical
painmed sinwltansoury
srith 03% OMBA
in tminasl oil
170
yptnt nv,rked reduction 138
of an:inot,enab;
11%in23w.eks
instesd of t7'/, in
9 weeks ie controls
1-1.5 uo effect on start of 103
trontbt arc:noBensan; wnr
dowing of tumor
Vrow11 and deeRaw
of numb.r of tunocs
13-2 !n intact euk 172
awmlr aniattls, wto
uerom d.arawd
oreinoma
fatmlios .
1S-2 Fn DMBAdreatad 1?S
ntosUt snirnas 3.0 tuews
pr troatad poucl;
with eonisone,
0.(+ tunan per
vaud ooucA
d moatbt no eAect (probably 171
eeaust with DMSO
the apent diaappean
rapidly from site)
,
I
CY! R 1/ i V' I ti m v M V' ti/ 2
b
Cltemieal Carcinoienesn in Syrian Hamuers 109
T.N.I (eant.)
Substana uudied Route Atwhata{c EBanobser.ad Rafersna
etteinoptl
iivta
Vitamin A
Vuamin A (oonoen-
asuioa tatspec;fied)
Orinted topieslly
with 0.3% DMBA
tot~ 2 atoe8e; aeaefar.twn ef (w tYo ttut
Vitamin D, nd D, topidl 2-2'/,
months
AatilympAacyu teram
Caxinopn DMBA intrs 3-4
0.3% in Navy proritAnrl wionthf
enineral oil AL.S
0.13 m!
Lytowtie aBenta
DMlA 0.3'q ie topial 1.5-2
prrsfRn; months
CyclophapAamide
) S%
Metbotrwte 0.03%
Vinblutine 0.0223/.
Ca{oryrantune topeal t
Baeillm Calmtxt+wGufrie tysteteie t
ttunor focmtttiar Wnr. (32)
!ae etor~
rewoot OaPv)
132,131
inAibi.ionoi We+a 67
farmation
..rlier nnd mors ri
traquaU tumors
with nrxt malrpVnt
cJuraeterittia in
AWrated lumstaf
106
qwtutteablt tua
prest;ioa of earoneBc+tesit
vuatia+.b+e «nr
Oeetiion or e~rw
PM*
marked utRibitiee
of arcisoPa+tas
following pretrtas. 103.134
nrnt er S itA rin.u.
tan.otr trtatenK
marteA iMubn,oe
oudnoet+te.
or
10Aibiti0n of .3
nrcin 4ene+:
C T R. M N 0 4 2- 6 8~`~
Howniaotn 1 t0
,
lack of svrpwl imt:rrention, nmintenana of oontinnons direct eontut of frah un,pla
of the tsst subttana with the buaal tntrcaa and easy manipulauott for tspestsd
teptusments under nattnsl snviratttrat.
B. Histochemistry, Fias Stnusufe, Cytology
Bw..Ap.vu and Ltlrwaa (ta(: Eidhty-tonr Syrian Mnncas from a local etoud
colonr (both uass) had ths Mft t9+uk poucit pah+te+d with 0.5% DMBA in acstons (how
oAen noe stand). wsekly erotoBieal aaiqn .rn nnds from trsated and untrnted
ooxcha. Acid phaphatass vu ttKasund by the method of Taans (1934). The msthod of
Feutts+t and Rotpsnbaek (1924) w wsd for a tren:qusntitstis aneutnent of DNA
activity. hrallel ttudin .ere tnade wnh hpanit:olaou's twininS Lehniqus. Durins
nuliSnant ar.mkirntation Metsam M phospltatass activity were obeerv.d. DNA in
parabasal and intsrnisdiats alt t~pu .a ineraafe4 in dyshariotie sdb.
Det.uvu sr.f. (2s, 2$): The rtBular painting of the roidso hannter'rci+eek pouch
with DMBA resulted in epd.rnaid aanananas. As had been prwiousty ot>served, there
oozvrred a marked diserpnisatioa of the subepithelial rncvlar systtye of the povch with
the dsvetopmsnt of a.uwlar syuean at the ttte+or ierdf, which oonsisu of its o+m newly
formed veudh tnissd .+th Nou of the hect. Tlwaa tAatyn oawr very aarlY prior to the
tumor uwmind inrasive charaa.riatits tto ler importatft, @r loalistioa of ths arisini
anon b determined by the diqributloe of the vascvlar tnt 6tte strttetural and functional
teiero vnits tor which tlr tant 'atuio.' h Oropoud. (Autltoet' stttatttary asmlatad and
condensed by trria'rer.)
FtwMar and Gua+t (401: Tha ebsak ptteha of SS Syrian Soldea han+tun aa+t
O.iated with a solution of 0.6lG DM1A in Ar*!M° :wioL a.mk. 3n+san were taken prior
to " p.:htinS and Nainad by Ur hpanie>otaeu method. Tba aeimab wm killed aftr
1s weeks. Sqtta>tww ed1 anranomat dsrsbpad ie 21 aninuk. Tlr Mt ehsnter of inMm~
atatiat were tren after enly 2 paintk+=s. After f-i paiatiNt abeortetsJ iquan+ots atb
wera atsn while dininl ahnoranRty vas onh alij*iq arytlnna./lftsr s0-13 oaintinp small
papillomatous powln .ert visibla.
Gauat and JoM*ao!+ (lt1: Twttoun woes ieduwd ie dtask poudtts of hsntsters
llNueerieora nnato) by Uaia..aaky topiesl ap'0)iqtiorM et0.3`ti 7:1241imatHylbenr.
(a)anthrsoa+a (Siptta, Londoe) in liquid oaralM. Siopsias wvs obtained from Nrs
anitenh every 2.eeks, preaeNCd for IisAt mivasopp, and asaions wined by a methyl
Veen-p>roein method. InAanvnuory odlf is ooneraira tiwue trtdar Matsd epit)rlium
and at Ue 6asa of de.eloping tuaroun w+ts muntad ie a toul sample u.a 043 101 mnN.
le untreated daek peuc)w, oounu for eaarophqr and lyatphooytw sae 1l.Sa S.a and
1.isa.d. retpactieiy: aMr 2 weeks Irstmsat with DM1A tbrs Yter.u.d substantially
to rO.S.d.2 and dS:l.d. rsspativdy. Tbsra followed a quiaoeat period, durind which'
re.aopl7aps .nd IymPhot? us datsaaMd ie Otunbar while ths epilJsalitus bsnmt prope-
dwlY Aypu9iastit:, Development of twnoea both seniin and euliptant..rat eonean.unt
.vith a suess and s«tndy riw in ths number of s+aerophade Cultninatind in wunu ef
Sl.it 1t tnasropha{er and 17.1=t.1)ymphecyte, in eareinorew at !3 w.eU. Ths upu-
fiesnaa of this variability in InAunmatory odl pattern ir sot t9ear but might be tslatsd to
~oat rss+wnw to wmour dwdoptrnnt and to ah. rarity of n+aanassa in thn sapersmental
.I
l..r f R { f i"f S--d' "i 2664
QKmial Cardnoasnetis in Syrian Hatraues III
modeL How..n@ the immunolot;iaUr priviktSed natus of tAs hanstsr tdnak pouch arka
k di!lkvtt to spuate the obyervsd tissue responus to stimilu phenomena alwwhta..
ToTO and Sw.ntu I190): Eit;hteeo ark4ared (atxonrlanic whits) albino haenttr%
30 days old. wtre trssted with 0.1% DMDA in minural oil. The ri{ht buaal pouch wtu
pointed twice each w.ek. Each w+ak. for a period of f wts, two animab w.n killed
1! afta injeetion of tritiated thymidins. A bOcling indea of lalclsd basa) alh was
determined each w.ek, oomparittS the DMiiAiratad with the untr.at.d mntrol potrchm
The stunbcr of )abekd allb in the control poucfia was 106/1.000 adttt wAee+taa tlsW wmDat .
was 72f/1.000 a(b in the DMIA-a.atad oouoM. DMIA ftnibaaly ieaafad ty
wmber of edb aetarinS DNA tynthnsis.
v&jtutvs and b/uavaewra (1!)1 (ar alw pp.116): tbe authas ataadi.d t!a
daaomotenic action of NMU an the tauaoa of the thaek pouch k1 Syriaa haarw+
(IJ01 Nr+plasen of various watintioa developed in 20 of 2s animals whieh aurriv.d
the period of appearance of the Mt twnor. Naoptuau 44 the aitt a( adtoinistntios
(m the ktft tdtak pouch) developed in 13 Aamt;ees (52%) aad i.11(s4lG) ts.es ardoprd
tunwn in the atonuch. Twelve n.op(aanr of the ehak pouch see tef<s.d to by th
authors as ernbryonal rAaOdomyos4uomn of rariots Abm(opd untetwas.
Wtrrrt and Spnot (196): Normal epithdial a(Y poea~ar tpaiatisd (nwvlMdar
attaehrnenu all.d desmosortrt:. Malignant epithetial aJ4 are thought to aldlit a daraaW
ttleat of intaaAular attuAmenti whieh s+igtt aacount fot Wa reduced adheirenasa of
tuma alb. There b erida+ce that In aWiSnau aW the number of attadmww Y aip&
lYantly reduad, but obtervatiom harr Oaea wljacehe,.rith IittN attsmpe at riuantintiod
Sawmow cell arcinomas .ere induced in Soldea Syriae lttma.r ehak pouch during
Uvioewukly application of 0.lSG ot7:12dinxthylbaat(aksatAncana (Siana,l.oedon) in
liquid paraAin. 8iopties ltom 3 trutad and 2 oaurol aainuh wae proaa.d for IlSht
miaaacopy. Adyaaat tEuw was proo.a.d fa daetron Nnoseoqy. Feoa.laetron tnicro
graph morphomstric methods .en aap{oy.d to ptintaM tAt total lenplu o(suya6eial
and lateral plasma tasenbranes. EaaJ 0(arter .retkratt., dwmoam+r and Aanidamoa
aona in 40 normal and 30 tr.ard Anal otdb eslaetad at taadoeR Maat "WAta wn aF{eiM
ant at the <0.01 ks.el or kst+ and wnetud tDat, im etallpt;nt Oual oel4, the tota) kendtA
of dasmosoma and haeidamoaonw .art d.n.naed, whea oompated with normal alY.
The da+sase in interaUuku auaettaienta nuy h as.oeiuad with Seater aLL mobility
accompanying invatioa
Wooa and Swmt ttftl: Hatsteasce traand a i. tia ako.t p.ptar (Ne.1fi) .hl
DMDA. Dioptiei of cheek poudw .Met+ studied by aioetrott tstiaoeeoqy. In tAt pea
malidnant coedition. epithdiaW aW formed papudoqodia, sither at ths epithelia)eonnasxire
tiswa junctioa or SrowinS into lnaaepithdht tp.cm Tket paeudoqodia were no lonller
d[stint;uishseM at tha omet of histologieally neoSnieaEk aaar.
C Modifyinj Faaton
D.oww (1S): A atat7ad study of prolirsration kinutia (aL cycle tim.) af oMmiapy
indutaed sauanwus ardnomat and of the eorma+l eptbdium of the titaY pouch of tkO
Syrian lumster. Sswal difkmnt mctlods, using tritiated Uyrnidine labeling 1n ri.o and
wadard autoradioSrsphic tnclLSiQue, .Rrt employed to mt:atws the parsntctas af tda
. LJ' TR H1 / 7..a' 42i..a i.+.i' 5
I
C
I
Sk
Nowsuu:a
/ 1
I12
cell cycle of t1>c normal and nQlipynt a14 both Wore and aher irradiation, Th! ,r,qn
length of the cell t:ycls of the tumor odls tras found to be approttiautsiy 12 h and the msan
Srowh fraaion was suimatsd as 31%. From a axnpueon of the potential doubiint
time of the tumon with their nrcasueed doubling timt, a n+an odl lM factor of 0.73 was
latimalod, The ran~e ef aluot obtained for Me all eyds time of U& nt, mal spithelial esllf
was 130-132 k .
Following itrad'ation of the tueara.ith dosa of 300 or IA00 rads it .as found that
the all cycle tier or the proliferating esll, was slightly lenqthawsd, the elongation being
primarily a nstdt of ineroaxs ia the durstions of ths G, and Ca, ohases. On ths other hand.
the same dotcl delivered to ths normal epthelium produced a 2033% shortening of the
call qrk which Osrtaisted from 3 dayf to approaimatsly 3 wrki after irradiation. This
sAoruntnj waf almaat auireFy due to a nduetiou in the length of ths Go phase of the «ll
h'ek'
Powsrtc (1301 studied the uRaets of high dew af radiation ea DMiAinduoed
tumors in hamstsr drek pouches.
Dw:,..w n d. (3a1: Attsmptt were made to derdop a rstiabls test for the proenee or
abarota of areint><stq in ehs environnrnt. Certain pbnt mawials wspsned of artsctinp
the developmaH of esophaSrai anea ia aun were applied to harnttsrs' upper pstroo-
inustinal trset, indudind ehssk pouch. in several long-term s=perimsnta. The materials
tssted, often with calcium hydroaide added, .m ! ptanti from Cur.oo used in nativs
uw and rsmalia, a tob.ae tis awtT), and an alkaloid (ar.aolur) psurnt in (setd quid.
Lsiot+s dcxlopins aA.r tnsueaM +trici the plstw An.ea wkyrs. Hslinryr,rM ie+sarm,
Kres.rr:n lstws. and Aeai. .ipw...nd .iwh aneolint, wae a trqKrfieia) spreading aa
cinoma of pouch spthtliun4 papipmew of aopluSw (4). and advanced ltytiaa (I in
oout:h, 3 in esophaSus). Thens Isaiona desloped Ia relation to ths dnsk pouch twa of
appliatian only. "ls norK rewlt.d after i.igmioa of a eohaaKnted ta fAar+s .t!lesaJ
or when admieistta.d in the diat (Aww .o.icw.. aneolina). The histologic types and
d'stributan of the lesions in ehsk pouch and so4hadts auqesad that they .ere aused
by substances in the tsa mataia4 tssttativ.qr presumed so bs.eskr or aloWsr in action
than the kmwn dmmiat areiee~aa.
Gwxt. sr d. (r3): la.rrmoaupprMiion (aNilqmpApeyfa urym, ALS) should
enhance and immune stimulation (bacillus GlmmKGut~rin. BCG) should dday arano-
dcnesia. Using the dinrahyl battanthnana tDMOAFbuoed pouch model system for
ehemiai areinoaeneait, 94 bamaters wwt di.ided iato Sroulr rtota++dt+= DMlA alons or
DMIA plua normal rabbit swtte4 ALS or !CG at two dosap Isrsis. After killin{ half
of the animals at 1 and 12 .mks, aeh pouch was asamined biuolo{+ally, and .as ar
aiSeed an empirical soors repretcnutis ot the most advanced puhotoqie chanqs. Sutisl tlal andyzw a.R
performed. At II swe#t; naultn sho.r the ALS group greatly enhanced
earcinoqatcsis whereas ths iCG pouo of Srawr daap retarded aroino>pe*+esis. At 2
wseks both dCG Srouftc retarded aninolerrsis. These results a+diats that ALS snhanas'
DMiA aeowoeeriesis witataa a wlRcrant doae ot DCG delays it.
Gtusrta and S«at.wa /N61: The eR.et ei'sritemiolly L+)onsd antidumster tympho-
eyts serum (At3) on shemicat asrcinopeneai. of the buowl pouch hai been ttudicd in
30 Syron hamstsrJ. In 10 animals the risht buaaW pouch was pointed with a 0.3% wlu-
tion of l,IOdarKtM1.1,2bsnanthrfa+r (DMdA) in hary ntinsral oiL Ttn anrmah
..n psinted with DMOA and also injsasd iatraparnarally with O.dS mi of ALS. The
..
2
I
r
':~~
i
C rI~ ! 'e I l - 0! 2_6-- iW
/1
!
i
Chemiest prrinotenais in Syriae Hanuters 1 u
r.ataininp 10 anienls served as untreated rlontrole. T1ere was a higher ineidsra ef ar-
einoma In the ALS/OMflA group and a supeuion of sarlier tumor developmanL Hir-
soiopially, the ALS/DMSA group presented a consistent tuma prturn with more deep
invas(on and more anaplattici+y than the control group. The poueAes of +he ALSlDMEA
proup .are more e:ta+sively involved in the development of neop4suc changes. (Authors'
abstract.)
Hoaw a.l. (12): Tumon wae induad by DMDA painting in aa nule Syrian A.m-
wrs of 90 p body weipht. Eight was left untrntad as controb ; the oUrn reaiv.d 2.a00 R
sa a UnSse aor to the tumor.Daney auek pouds. The irradiaud peuehei ad the oa+w
trok .as ssamined 14 and 39 days aft.r radiahenpy. Tfrn was u+llanunation and
troosb in all uqted pouches. In 13 of 14 treated anintab the hm+ora had diupptrred.
tn aU haeuters asseased 39 days after tnument ths tumors had r.etirrad. T1+us, tM ob-
aervation period in esperimenq on rsdiolherapr trwst be long enough to ae,lude t.At
poafbility of r.autenoe of tsuaoes a'Aa initial wppnstion and apparent wra
Lavu rr d. p0)): Ffty mak Syrian hamsean 11'K nanthe old (33-d3 S)w uad;
70 of thaa wo ewrated. Two welu fater. D1NDA applieaion to the d+rk poucbs
wat iniliated (0.3%;n liquid paralM, 3 times p.r sek (or up to if .eeks/. Castration
Aad no eRat upon the ini+iatia+ of ti+.rniai areinooenesit and dwf na deb
the
ar
-
y
-
appe
`j ana of lumorr; bo"ver. the fu0uqueyu rate of tumor Qowth w.s depras.d and the
twmber of tunwrs Was ndue.d.
Lsvu and ftttuut (1041: L.oral trwtnw,nt of bantper t;ltaek poucha with 30%
vitam6+ A paimitata in liquid paraiRn for 12 .et:ks rerultrd in epitheliol cMfta .iueh
.ve rspor+ed ariier, and in addition in the formation of deeaa etononuckar oiq in-
bhrata in the lamina propria and muscular wall of the elntk pouclrL Thae inRlnaul
.ere oflen nodular, eonsis+ed of lymphocyta and large irre;u4r monoa,dar alls, aad
wrc rsnunocent of chanpcs found in asaliptant lymphomat.
Vitamin A hat boen reported to have adjuvant proportia, and the menonueku aL
iniUtrata may be related to damage of lyn+phoid all membrsnea esurM by the vitsetin.
tesulting in proliferation of immundosi[slly enmpetenl ae4s.
Lavu and PoLu.ctic [103): In pnvioue etudia, she ttQ.a of n.mbrw-.ai.o tub.
stances on hamster check poucb arcisoma induad.rith l.10-dimnhyt1 2~lent,atAruat
(DMNA) was investipted and k.aa sho" Iha/ topical vitamin A pslmuats rewlled in
ineeeascri tumor formation. It was proppod that tha eotattinopene dleet mipix be
rdated to the membnnaiabs7isina propeltia of INs vitamin. resol+n+p is aaavaian and
release of lysaotnal ensyms, shieA a+ay play ae important role in the iaual esaprs of
cell division and tumoriDenais.
Subsequent studia. tsins the nanbrsae-wWiti++p apents oonhon, wnte and
dilorprortuzirK, knewn to wpprtsss mftotie activity. dsn+onttnted inlubtwn el DMOA
esrc,nopenesis ia the hamster eheek peueh. This eR.et .n interpreted as banp rdaud
to the mcmbrat+e-stabiiizinp properties of theae,renti
, In the pnssent study. ths e:?ta ef dtr above ewnkraa+nive wks+anos on the
rnito+ic frpuenc7 was invatipsed in normal and Db(OA-4reutd hsmuer ctteek poueh
epithdiuet, in order to detsrmine whether there b a relation ben.een Me c?at of Mesa
wbsuners on the mnpic frequency, and their promotion or rohibuioe of nm+or forrnation.
PuLu.cx rt ol. j1)1): Tunan were induced in the eheek povcha of inuct anJ eas-
trated nuk Syrisn polden danx+as by repcateJ topicsl aM+liation of 4.14Jinethyi.l,2.
tir f R { iN 0"/. ,. .fk 68i
Ha.nvuca
114
bentanthtaane (DMIA). Hall of the anitnab naired in addition intramuuulx in}ee.
tions of tsstottaona propionaw throu{hout the uetmant with DM9A. After 9 and
12 woeks of utatmau, spuaaroKs call arsinomu were reduced in number among intact
animals receiving DMOA combined with tautttaone. An+onk aatratad animals treated
with DMDA and tatoatsraK, there wers hu ttuoors after 9 w.eka tAaa in asusted ani-
mak treated with DM/A only, but not after 12 .weks.llw tvma ineidenee in intact and
aurated animals trat.d with DMIM ony .as wnitu Utrout;hout the ape*iment Thus
in the pment modd Nstouarone appeared to daeean areinomt lonnation in iaaet
tnate anirtab. (Autb&s' aMtraet) , -
Pot.u.tex and L.avu (1)2): Thirtyfivs Syrian golden luerotas, apd 2 months, wen
paintad three titnq a.esk vith either 03% DMDA ia partlbn or 0.3% DMIA com
bined with 10!: .iunrn A palmitate. Half ef the animals of each group .ers sacrificed
!..eeka after the a+sn ot trotnteet, the othas, I Iwesks after the aure of trratment.
Larger ntrmbers of tutnon and more m.liSnant ttunors.on found with viusmin A added
to DN1A than.nthout tae vitamin.
rotat.ci and Lsvu (1)7): Fot:i of ietraepitlKlial ardnomtu anaEeni/n palallomas
up to 2 mrn in diamasr were pretient in the ehsk pouclw of all S hamsters sacrificed
immediately after eanplaion of the loeal tnatmentwith 03% DMSA in paraffin during
a period or dwaka. Among i haniasrs trated similarly but taeriAcsd 2 months aftar
diuontir.ualioe ef t!a kxal applidtion of DMItA, enlr 7 showed beni/a paplloma, aed
uo avanaen ... ReePt Of the f aaiuria nerivint DM)tA f« tt .ska, followed by
locsl appliotiew of pralM for 2 s+ontM, aty I aAored a p,piUoma with intrsepithnlial
eucinoe+a, aw1: w r.nrininj 3 ashnab ne ttaeon .ae fow+d. An t arwnah noeninS
similar ttiptrnaM wth DM1A euring f.eeka, followed by topial admhtittrstion,(10%
vi.sc.L. A p..aitar in oaral6e durYt/ 2 nosslr, abow.d hdUtratiwts apuainow an
=Rbwff,ML 7tie aOithN'rl ebnpa induad vitL DM16A dtrinS f.ab thus nr sssd pnisCy
when appliat'vft c! Ihe areinope .m discontinued. Howew, tubaetsuent trntmatt of
ther ktaiau .itf vitamin A isdnwd an iw.ne b sta asd arliptant~r. Thi. eR.et of
vitamin A mq !. relat.d te intaavd pvar.billty of aUulat and wt>esllular e+emDranea
with t.aultin/ ine+.asad pamratioe of the ateino0es into etllular struetussa. Ho.erer,
since the admiewreaion of DM1A.aa diaeoetiat.d prior te We appliation of ritamfa A,
tht Andina oro0al12 rewlted feont a dir.a.}I'aa d.itanw. A ea tmtal0olie prooaaea in
ep"lal ee4 which bad previously ksa alwed by DMiA.
Fau.ct ur tsw )134): Haersw dwak ooudts stt treated topiaUr with
DMU alona, s eomeieatioe with elstorproautt;ea (etz), er lolbrinS prevat,nset
wita t?L
Alta l..ia ef appiiatioa of 12% CtZ aat103% DM11A dntottanooutlr, only
etr aiere~oets fean of MtraeOithtdial eartanom" was praent in I of the d utima4.
wMr*ar ita the d aninnla tratad with DMSA abna, niot atrpid papiUomu tndlMe
invsiw ardeana...n prasat. Altr 12 .eeka, odr on. oroeoma and one atYpNal
papiUortu ..n foued le 2 of ths f taima4 trat.d with CTZ and DMIA. in oontraa to
Ms fhtdinS ef I/ ardnomu and t atypiai prpiUontaa in the poudta after DMlA alons.
The dou., 6W aR.a of C'9Z was dseeorutrattd .Aa'n. ie a similar procedure nth
0.ti% QL Kt2 prsal iMibidoe of osranoma forntatioe was obtaiocd .Mr f and
12 ..ka.
I YL'
~a alllr/(`t
AR
CTR MN 042-688
rk
Chemial Carcinolsncsit in Syrian Harnqers 1 t S
M+hen the poueha wu pretreated with topial 1.2% CPZ fa 12 wekt prior to
~-----°-
I ., 1. rr+~'~. ..rw.. .......nv.n. M .YnNf .V.- fql. wiY ~.lAY.
+` The antineoplutie aetion of CPZ b rsriewsd snd the membrane and lysoeomal
wbilitinp propenies and dow relation of thie drug are discussed. It is suggested that the
inhibitory eRen of CPZ msy be related to daansed permeability ot cellular and sub.
~: o>alu4r numbranes, re:uhinp in desnar.d pernxation o(the aninojen into the aellu4st
uructures. It is also potsible that usbiliration or lysaomea Is sehieved, with dernssed
~2 releax of lysosomal enzyena known to inA,w+oc turkar aet+vity and with oortw7tasnt
~ . ~ delay io aU dirition.
zt tau.pt.r d (f 2S(: After topical treotmaa of 6arontr drk potKbw akh DMlA
:' sad oenirone aatats for 12 w.ekt tM asnps yield of atusinonua per t+.ata0 tdtaah
pouch wu 0.6; after treatment with DM1A only, 8 was 3.0. Dssrraee af ewnor tonatioa
atln cortisone was probably due to dspnasion of DNA synthesis and tuitaic ata'rvity by
.. the lwrnane. Cortisone stabilius biological tranbranee: its atxiott oa od0 owldpikr'ifs
rnay be rNated to desreax4 mernbrsne peraraafity wijh t:onestlusat "bition of rsrwae
of lyaeeomal s.:eyma which p4y a part in early st.pn o(oell division. DaRated eMrnlrarr
permability may siso hsvs rewlted in hte eftanive penetrstioa of aranoees fnto odh
Rewfte an in asowdana with thora of pneviots atudia, which danonstrated promo
tion of tumor ferntstioe by labilistrt of biological tnembrsea such aa vitamia A and
estrogen.
ro.wnto and Co«a (1)1(: forty youn= Syrian hanrtan tnatctKdtorw.iplttaed
M received identical diets ContaininB 21.! ppnt of ttinc. One group of 10 tt,oeivad ttiee
twppkmenn of 100 ppm of Anstar sine wlfata ia the drinking waw. DM1A ia hpuid
panlftn was paintad three times ..ekly for 1 waeks. Tlw nuuhe ehowed 13 of IS animals
in the DM3Atraud group with tumors atter S/ w+eka. Only I ot! animalf teaeiving
zinc bad s tumor after 15 w.eks. In eoeuau with Lm injection in FWta3as rstt, arei-
nonw developcd in 24 animals. The first Manpet of inflanu+wion were faa afta only
2 paintinp. After M paintinp abnormal ayuamoie allr wera saen while dlnial ab-
oora>ality wu only slitht erythrrna. Afta 14-IS paintinyt oetau papiUorouotr QowtM
oaa risibk.
14Notau (1S1J: See papr 107.
RuaN and Ltvu (1S7J: Local appliatia of vitamint D, and D, caused inlsibition
of tumor formation in the hamster ehotk pouch, induced by topipl tteotnrnt with
OMBA. Thtu results and data from the literatunt are used in an attempt to eapLsin the
atichasiam of amnoSensu by DM BA, and the iMitrtioe of ahif proaeaf by vitamin D.
Ie tumor afb the amount of slkaline phoaphstm and the anouM of mkiwn bound
to the oell mernbrana are both d+craeed. !t ie probapk that the protein molocuk alkaline
plwtthusu aa also aa as akiun*bindisi pouia T'he darwaad amount of calcium
bound to the mentbrane of tumor calls lesdt to inerased permesbility. with an inersssed
and ku controlled 8ow or metaboliue to and fran pte eytoplaset, r.whinB ia a dtacreaud
control of the mitmie proeaf.
Vitamin 0 causes indunion of the fyntltaeit of alkaline piasphootehakiurn fwadini
protein. and thir may esplain the atarked inhibition of OMBA arnnogenau in animsb
trested simultaneouely witb DMBA and vitunin O. This ettat of vitamin D ie probably
not r.pecihc, and tfien are inJiationa that other substances which cause induaion of
alkaline pttotphatate also inhibit tumor fort»ation.
trr
L
F
1 ".4
CTR i i f 7 '.'. 42~«.A Bq
.
1
t
Horsuaca
116
SMttt.wts 11701: Sixty rnaie and fcnuk folden h.muere, t nanths of ape. wwe studied
for the eRaets of Incision and nulnipuouon of bucest pouee ardnomat upon'tM grouth
sad invnion d thae nulipt.nt tumors. Epidermoid qreinoreti .rere induad in the left
bueea) poudt by psinuq thrse tirrrs .eeky with a 0.S!4 solution of 9.IOdimnhy!1,2-
(ancanthrsean it hnry min.nl oil. Carcinomas bso+ne poaty visibte at 12 .aks. At
tbis time, the 60 animab "re divided into thne oquaJ groups. In 20 aninuh (jroup A).
eo further trestntent was arried out. tn 2D animab (iroup 0), the left tuccal pouch was
everred and a 3-nrn ineuioa st made in the arr ot Natholo;y. la 20 aninul. (group C).
the kdf pouch was ererud apd tM tiwu tnasaped and eompread with a tissue forceps.
AU snima4was aserinoed at 11..eks tVe paa or tniapeeopie diRerences'wore obtened
bsrween the Wse Sroupt in rettrion to tumor siae, Mwuion. ar e><temion. Metutaus .at
sot observed in any ot the aroups. (Auttars' atxvaa.)
Saon and S+uawa (1911: Syrian hatntsa, ti aronthe of ape and weighing 2!0 p. .ere
used (both acsp, tq at dilkrtnorr obsert.d). Gndaoaen w 0.3%DM1A in minutl
oil 3 tfnw a..eka ta eeaK, 70% DMSO was added; in ethets, 0.023'A% triameinolone in
pevolatum wst added. AfMr 10 o.elu the animab .osre taeriAwd. The combinuion of
DMSA and DMSO produced few tunan then did DM1/A alone or DMBA plus triam-
einolone. In those animeb rotaviq DMIA. DMtO and trianrinolone. no tunwn *ere
obeerved. The retardation of twna fonnation is ateribad to the spit+dial depenentuve
changes indund by DMSO and triamoinetone.
Vr.nucvA and Mulvawtsv. (1931: 50 paps I11.
V. Ord C..lQ
MaeDaruie (1121 aad FaAwtcux~jdl) advocate the use of DMBA-
induad oral atcinoma in Syrian ham-t:r>< to reoder more objective, and
pefhrps of proptoatic value, the histologic Sradia{ of oral epithelial atyDia.
MAcDowAt.o found the atypia of human and hamster epithelium in pre
auliBnant stages 0 be timiiar and a good prognostic indicator, and FuNxuN
found nuclarjcytoplasmie ratios altered to variable deBrees in atypis during
DMBA eardnotenesis. Gt+n[u. (16J noted that human and hamster oral
matitttanciet are autogenic. While DMBA applied orally caused a:mal(
number of areinomas in the oral metcosa, it was impouible to induce any
cancer by application of snuff (16).
GNnat tlQ: Reeent werk tNwttt>r. R.C., w oL: ir. med.1. b: 701_70s. 1971)
aut7,pow that are;nornst of the ckin arr induoe iennwns nsportaes. Faperimenu were n+
up to Mat odimediaad inunuelqr to orsl ealipuneia. D'aweud piexa of tunwrs
obtained by biopsy or after eparalive resection twn eultured frae eaplana in plastic
tluka in a!!i earkon dioxide atmoepMa. Grorth of eulipnant odle was achieved in i of
I 1 aasa. Gre1s lestina by eapaurs of larpet odb to auteoAtAottoa lyenphoeyvs demon.
qraad that ertotosieity and c+oiony inhibition of tartet oells oceurred. Fibrobtuti were
ynaffetttd by the lyfnt+hoera. In an aperkr.u with hanstus, dinxMyibenantAraoene-
Mdumd oral orc+nomas was sueeessfuUy transplantad to other hamsursm but the mfer
lioa raw dto t+snaferwas hish. A noaoeytotasicity MoAaipue based on that of MckA.o
C" T t Z M N 0 42 6 9- 0
I
Is
/%
Chemia! Can9nototnis in Syrian Hanwsrs 117
w.G (lranlplantatioe /a: IsS-ut,1f'721 is being used to anea oau-m.diaud itnnrmny
by iewbation of labelod tupa a14 rith T iymphocyus from wtnorbnrinS and aynptnie
animah. Currant tesuUt indints that there b evidence that nuny hunun and hanrnr oral
esalipnaneia an antipnic.
fUwauw (H): Hutopathobpe.l asfasmsnt of premdipsant Iesioru in the oral
.wKw is mads dilRcup by iuufl9eient data os the aipsiRanes of atypieal fatuea ie
epithelial dysplasia and by their :upjativs intoptsation. R.csnt atumpu to imrodua
i
i
f
i
i
i
I
) h
i
i
i
n/frprTtat
pf o
m
COalop
o/
7 ~ 1101 1~f oOjrCt
nte
ratYrlt (0 oral tp
tAd
T
ty
unl (SwCTN
aad R>so.ono: XQs.lorkd Gnfuv olOr.f &irAdtd ArypN ty the Uir oJlAMNry4/e
= Si.Nara'r. HatnlxnSen loStryktsrt, CopashaSen 1!6!1 ara.a7l.omewhat auejaesi.e aed
'~ a,.aeptible to obrwer ariatioe. TMn wtera<s fuiIht he oraooaa if eytolopeal
mnss cww w quamnawu vvl.cusq. w pua ttiwy naf ts. Yavtsea to CMYuH IOt
!'i:r atadaar tytoplaneic ratio (NtC) in apithslial tsJb, a eanmonly quaad aiurioa for dia-
'k ' tin+uithinp epitAelial atypia which ahe landa haatl te arorpMmatri~ t(uaatiatiat. Cbek
poxh:, of golden Syrian hanusas wera painted Uvias w..hly wiW 03% DMIA in
Squ1d paraAln. Nonpainted poueMa from different hanrtert providtd oontrob
Sections
.
if:
bota hioqiea nten at
w.etly inwvaM wv.
r.drd listolo
iall
rior to
ha
r
;
:,
~
y p
p
on
ees
P
i°
Siphy of tsndom Arlda in nch raioa and pouu ooununS t.d+npues wae applied to
at patotoSraph+ (wusu. E.R- a ot.: l. Cell Riol. !0: 23-2II. 1fti61. The N/C ratio .vas
:: alaafaoad (or aeh puhologial uaoe. Rtsults indiau that the N/C ratio is or l.pthdia!
~ tsllr aa be nwaurad by ths lahniqws anploy.4 a++d that h h a)tar.d to vari.bla
ie+f.n is spitha4iat asypia produced by afsinoSeatsit.
Ha.waaa (7e): Syrian golden Mmatera (Illo RE ateain) ..ae wljan.d t days of
. .uh w.ek foa up to I year to ieunobiliratioe fe a aanchioa by tanna of a eoltar and
' iroettioa of a bit containing eid+er ootton or oatoe impeesnatod with DMlA or "
(a form ot pul.erised tohaooo) into tht SinSivolinpu! told. While tht polycydu; hydro
i
arboea, apeciolly DMDA, au+ad a fe+r atanoma of Ws onl tnuoo.a and a.raeh
4sAa numt+n of perioral stia anoars, the apowe to tobaaon aured no ehanp abn
.. lntensa tAaa thae faal is aniluab Oitins ofa COtf0Ae011taieinj tiits.. S11n tiponded so
keowe aremoSets nwrs readily thaa oral mu+ota and. tbu4 L the bat wa obj.et for
~. this kind of contact aeoinogenaiL
. MACDoKUO (1t21: t1>e tur:stntset of putrl+P»at bioa of on1 .pithtdiuaa
praaenu a diAticvlt problem for the diniciaa aed the pathoiopa T1r prognostic qlue of
° the ohjaaiva asypia worinS aehepuw of SwriN and tno.oae (Hia./arioaf Gndtp of
or.l f.Itrblt.l Ar))ria ty rb uar o/Au+lrvrAfe Suni.dr, 1f69) : still being awwd
Evaluation of huassn mawial auaa t+aeral diR~eultio that taa be ostaorna by the tw
of a suitable apeimeeta) anoaaJ tutmr t)stan. Suebh tya~a was devised. Tho standard
tleehniqw for indualoa of areu+emas is tba hanrur eh.ah youch rpuv.d modi6asion
so loa4i8 tho 1lfpOMa 90 tiJCinojtn and aMOi/ ffMIR ulnt:lti0o. PNtlnaliyla.! IOi00a
nptlKtial
of the pouch wtis induced; biopry.perimai, wra obtained and enluaud by the
typia scoring tachniqua. The lesiom .v. folbwd to omrteWt Uteir proSeast with the
typia acote. Leaions that beonw nutipunt had aitinifkantly hioxr.typia scar. a[ tho
lieae of biopy and the atypia aooriey t.eMique waa thought to be a good prognostic
inJiaior. Epu1t<liai aypiu in humans and hamsten srr ahowt to be timitar and it wn
aoncluded that the atypu scoring would be a good prognoatie indiator in fauman oral
pema6vnancy.
tti..i r* ~
CTR 1 i i 7 042
N.
1
I
aW
Hom.u.cu
Vl. Toelve
11t
While most previous attempts to cause carcinoma of the oral mueou
havegiven unsatisfactory responses and especially the tongue has proved
resittant. FWitA at ol. (t2j have developed a method which proves 100%
lowful ir rwj- eziw- af!lti~i~tp
p~~~a
Qieminl t:arcinoSenesb in Syrian Hamuers t N
in the upper respiratory tract remained very low. Sin j1e subcutaneous doses
of diethyinitrosamine, ranjint from 40-0.3 miJka body weijht, were tested
by MoHe er al. in the adult hamster. Tracheal tumort were observed with
doses down to 7.5 rrr=/kj body weiSht; the hamsten were kiiled at 2Swecks
and the tumor incidence varied from $0 to 20%. A smaller dose of diethyl-
nitrosamine (4 mS/kj body weight) was found to induce a 0; incidence
of tracheal papillomas in hamsters followed for the;r entire lifespan. In otAer
studies MoMtt tt dt reported that tracbal tumors cs.t be iadt:,ed in ths
offsprinj of pregnant hamsters treated with diethylnitroumins. The authors
state that a single administration of 2 as= of DENA to pregnant hamsters
appeared sufficient to induce a areino,*enie effect in tke !n n:w
burn hamsters a high yield of respiratory tumors nn 5- induoed with a
single dose of DENA as low as 3.3 enj/kj body weijht, w;thout deaiasiti=
, yield in the dose response curve being reached.
Other nitrosamines have also been found to he ardrojenic in the
respiratory tract of hamsters : di-n-butylnitrosatnitu, rncthyl; utyln itrosamrne,
~ aitrosopiperidine, nitrosopyrrolidine, nitrosomorpholAne and Nnitroso-
heumetbyleneimine, dipropylnitrosamine, alkylaitrosamine, N-aitroso-
methylurea, 2-hydro>;ypropyl-N-propylnitrosamine, and n+ethyl-Npropyl-
nitrosamine. It is interesting that dimethylaitrosaatine seems inactive in the
induction of respiratory tumors in this species; no rapirato6y tumors were
observed by Dorrrt't+wtuu in a total of 120 hamsters treated wis ditncthyl-
nitrosamine. Nitrosoazetidine appeared also not to be careiaoreoie in this
species.'
Dowrt:r+wttt (301 and Wyt+eat and Hoartutt+ (104) desaibed en-
hanced bronchial metaplaua and tracheal papillota formation in diethyl-
nitrosamine-trated bamsters by subsequent atposurs to ciSarette smoke,
volatile acids, aldehydes and enethylnitrite.
Monrtu+troo (119) demonstrated that a prelitn;nary systemic treatment
of the hamsters with a rsiatively low dose of a respiratory-speciSt carcinoSen,
such as diethylnitrosamine, prepares them to respond with a high susceptibit
ity not only to a level of benzo(a)pymte, which by itxlf only appeared to
cause a weak carcinogenic response, but evea to an ino.pnic p,%niculate
material, such as ferrie oxide which had been atensiaty tested by idelf
, with negative results. Further studia by the same authors showed that intra-
trachal instilutions of ferric oxide alone followed by systemic admioistra-
, tiotts of diethylnitrosamine does not produce any synergistic or additive
eRects in the induction of respiratory tumors, but resulted in a tumor rnci-
dence similar to that found in the diethylnitrosamine-trtated hantsters. On
r
1
fl
C T R. ~N 0 42 6 9 3
1
F{
d.WRG. . 120
the other hand, diethylnitrosamine administered after the iatratrachal instil-
latioas of bettzo(a)pyrene and ferric oxide increased the number of squamous
cell carcinomas at the sitcs which have been shown to be particularly
susceptible to the carcinogenic action of higher dores of benzo(.)pyrene.
Each of the two carcinosens seems capable of stimulstinj the development
eY tur.,or ty},eS cht rrcuris.ic of tho direct t;Reet of the other.
'Gretr_utior ir required in tl:z histological evaluation of such eaperi-
meats, and those of studies of the respiratory tystem in jeneral. A typical
tquamous metapiasia should be clearly distinguished from squamous tumors
and lesions of the respiratory tract should not be considered as squamous
tumors unless tiuue invasion and prefersbly metastases can be observed.'
M.Ttwrr et al. (9) demonstrated that the DENA-inducsd tracheobron
chial tumors were not preceded by metaplastic epithelial alterations and were
more similar to sdenomatoid polyps than to papillary squamous cell tumors,
and Morrsts&r+o and Spmorn (120j demonstrated by means of dose-
response studies that the carcinogenic raponse of Syrian hamsters to DENA
followed a distinct pattern for the different segments of the respiratory tract.
TAscA et ol. (zE3j studied DENA-iaduos+d papiUomas of Syrian hamsters by
cytophotoeietry, providing a quantitative description of the characteristia
of these neoplasms. Species differences with retsrd to DBNA were shown
for Syrian and_Chinese hamsters by ALTtton es ol. (6J. Syrian 6oldea ham-
sters had tumors mostly of the respiratory tract, while Cbinese hamsters
devclcped Umors mostly of tha di=ative tttet. Tbe lateat period was
influenced by the dose but not the eaorpholo6Y of tumors in the respiratory
tract, stomach and bladder. Subcutaneous injection of DBNA increased
the rate of tracheobronchial tumor formation in Syrian golden hamsters and
also caused urinary bladder anan, while in Chinese hatnsten intratastric
treatment caused more forestomacb and bladder tumors. DENA as well as
DBNA are transmitted to sucklinj animals in the milk (117j and in survivors
cause hyperplasia, dysplasis and papillary tumors of the tracbes. More recent
work on various derivatives of nitrosamioes shows induction of carcinomas
in many orpns, including panereas, liver and kidney (143j.
ALnan 111: TAe h.er+a wu us.d ss a arodd tor syvArnrtie studisi in primary
nwluOle eueinopnaa induced by GB:4. Afur tubwraneas and UunWUic u..unwt,
neoplaser .erm unwl4anmmly taund in ehe nspirstory tystem arrd in tM urinary bladder.
A ao.e-d.orndsnt effees was san for suwi.al, twnor inadsnee and lsunnr. hodlonw
uwJ cpiderewid orcinomm sro tound in Ow nasal cnviiia: papillary polyps were nusAly
found in Un laryna, trachea snd stern beoncAi t.herw r".d and combin.d oranoeus
wre oherv.d in the lwnp. The urinary bladder sAow.d eninshional aJl p.ppUom.n ud
esronomai
i
i
C T R f l N 0422694
CAemiral Carcinofenais in Syrun Harnaert !21
: At.tMOn u.fr f2J: Syrian 8olden Aanwen was a.ned weaaarrously, twith N.
_ ~~,' autrataltsasmnAyknimine (N6Mq. Tumors of tAe rapirstory system .en found, and
Ue traMn appeared to be the main wlcc orp4 Neoplasmf of the naul ariue wen
^. tnoctly adenocsrcinonus. wAereas the morpAololie patunu of trscAesl trmas +pe
~~ .imiLr to the papillary polya induced by dietnylnitroismine. The lunp had a low tumor
~~ Incidenot.
ALnan er ef: (l): OaidaHon at the oarbon oaurred ie atetaboi'sm of d6tt.
Proqinitrasntine (DPN), previously sAo.n to be atrdnopeie for snimaY. 1MAen 2,Y.
dfatetAyldipropylnitroriemine (DMDPN) wm fnjeated to, orwrw wsk for life Lae tt+ta4
~: .nd fern.l. Syrian hanueers at krds ot f00, 2SQ (23. and W atS/kH body .rei{At, it
ieduaA seoplatna in the aasal e.ritia, k+ryn., 1rseAa, ond asrn lrondu Si.a tA.
~ p.unoe or s metAyl Srouv on the bnrson ruaated that DMDPN tould .ot wtderSo
.:' PotiJation, the aueinolenicity of DPN for t)wu oonirxu af ilk- rsprucZ ttaa .ns
p'obaay unrelated to boaidstion, though earlier taynimenta Aad itidinted tAe possibility
of this mechanism. 8aawe DMDPN failed te induot neoplasnr in otlt,t orptitt, tAe
., .
earoewlenicity of DPN or Its 0 mnsbolites for the lunSs, 6re. peneras, and kidn.rt
w not aptained by this e:periment
.
~ At.ntorr er d. (d): Dipropylnlaro.am3n. injected sulrcutsneoutly ones a..ek for
1Ne into Syrian jolden Asnnte+s eauseQ a 100% tumor intidenas in the rapiratory tyata.
The bAydro.ylated compound (2-hydrosypropyl) propylnittoaamins and the boaidisd
oanpound (2oaopropy11pro0ylnitrosanvpe, administeryd by tlst sunt raw and frr
)' quency. showed the saer eReeu. MetAylproPylnitrasntine inj.cted ltubetuaneoutly, oep
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1o.Aydroaylationo mnasolism by bArdroaylation might be.safooiNed.ith the arono-
8enic efTect or dipropyiniaoaantine.
At.nton 0141. (6): Qne hundred Chin.e Mntiun and 100 Syr(an haerten, 3 nrontM
old, from tAe Eppley lnttitutt breeding colony rocdred oeot seky, ffor life 300 st8/k8
body .ei/At of DBNA (6% In oGw oil) by stomach tube. The rme daee was Siven a.e"
to 23 animsls of esth:pocia (sea na rpeciMd).1. anieuib ef !pA laeie wrvi.inl loepr
tAsn 30 rakt morpAoloSially similar tumors or the urinatY Otsdder, fp.µan.d. orag
and nasal ariues oavrred. Syrian golden AsetWert tminly Aad twnms of the b.er
resPiratory tract, rAile Chirwe Asmsten derelo}+ed tumora mostly of the t6lstive ttact.
71te morphology of tumms in the rcspirstory vaee, taomaeh and bladder doa na depend
aa Nte ror+te of nppliotion.-Aid+ inlltrt+ws only Ur Isunr priods. Su6c+naetors N.u
teeet with DlNA incrsnse the rate of tracheal and lrondtW tumon is Syrian plden
Asmstert; in CAin« Aamturs the tumor rste in forsromech and 6laddr b enbannd by
iatraWtrie tratn+au.
AiT>toir er sf. p): After s.e. Usate+au .'it* NiivotaAtasmetDylordw.e. Syri.n
golden Aamstsrs showed m.inly papillary turtwn of the trsdttz In Ss iu ruice, the derel-
opment of lung aderwmni irat slightly atimulste4 cemtlrrd.itA oomro(s. Tlwe esperi-
meats have sAotru that a sinale dae of 1 aK/k8 k. el N~aivwolK.arnetAYlnteimina ir
sufficipu to induoa tumass:. Ue resp.atory a~tan of Syrian 8olden lunrtt».
ALtttorr .r ef. (/): The owot;enie eRew of s single daee of N.+fuaopipsriJine and
Nwutrosomorpholine wen examincd iA Syrian SoWen A.ntWrtt. The main tat{et organ
tras tAO repiratory:»tcm; the majority of neoptasrro was found in the uuMs As ultrs
uructural invauptioro could conrwm tAe tneAesl tumors were polyps. Swfacrfinin8
I
(r f R { iN 0426...a .. f
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tumor edts as wtli as etib In the lnterrr~diate epithtdiN layer still diRerentiated into
ciliated and gobtat a11s. fn addition to the appniana of neopfasrns, hypt:rptauic and
dysplastie changes of the tracheal epittuliunt vKes t+ati+.
At.nan a of. (91: Diethylnitraaansintt-induoed altarstiont in the tracheobroneAW
eystan olSyrian golden Iwnwen,r;rr% studied rich tnn`..thin t.ebn[.ua. Fftperptau_ and
dYSO4a+a of Ih. epiU+eGum ewM.' 10 txrcai. pe.tdriu, Wn,.* dt..k,tn.~-r. These mor.
pholo`iea( patternt .n:P ttr, :U b.rtlw twrwW a,.itlAtnt. tividnA% was found for
rntaaplutie change to sauamots Iepithdiunt either ia ths alues! aaduobronehial or
tumor spithetium. (Authon' aburan.) ' '
Haa et N. (33): A total of 320 fyriae golden hamsters (Mraenirrrrr a.aw) ..as
treated subt.vtaneeusly with tswNth. aw-tent4 a one.twntieth LD« N.nitrosonorpho.
line (NM), N.tNtrotopiperidine (NP1, N-nitraomethylura (NMUIL or dinrcthylniuo.
aYTine (DMN). Tht auanopsnirily of tAa eoanpovnds dtanorrtrat.d telacti.e or=ano-
trop'sm. NM. awdl a NP. Muhad in ti3-tOp% tndteat pt,pltary tumors, dependent
upon the applied doee level; AoweKr. NM induoad a liEher ineida+oa oe
tun»n in the
nasal arides than did NP. A>lialu sRea was obaersd ia the lunp afier treatmem with
NM. NMU inducttd up to 63% aarcomu toalisad at the aite of injation. and in'fA of
the nainub papitlomas e( thM forstotnuA we wen. With DMN appiiation, orerlappin{
hcpatotoaic and earcinoaenic ett.a...re observed. Lo.v dorr ineraaed the aurveral
tats, but tuear Yreidenae .~a rsduotd aNy . itA the cydit: eorupowsda.
Mowt aud Aan+wy (1171: fia-esantleld Ate>suea.art tt+at.d dlRiep their lacta
tion psriod (1-30 days a(ar dtdivery).itb se. IttJatiotr of 3,10 as,d !0 etSlly body weight
of DENA d'sselr+d is vatet, or 300, f00 aed 1.200 rrtt/ks body siaht of DDNA in
oiive oa.1s the tr.at.d tnothsn, foal hyprvplwio and dyapiastito alqration..w aen in
the axha and nasaJ avhy and all of tMn+ lad trat:!>tal papitlary tumon.llVith DENA
th.zs we also easal papll.ry eanot« 1;Kyill:ry tutnon of tacMa and twal a.ity
de.8op.d ie the youni of DENA- and DENAdnaad reothtrL Laioa of oRitxintt
eiaelr reeroblad thoa or the mothers. T!e arcbopatit: apwt t.a.im to b. danorurratad
ia Ma ruilk.
MONa or ol. (I 1i1: =yriau poldt:e 4muars ..es traad w6ils nunini. Mothers as
s!I as oRsprmg de.Neped tumon /a( tAt raperatary aystan. Total aurneer of neoplasna
increased in the F,.penvation as dae Si.a to the PRprratioe ine+ard. Prelinunary
raulu have shown tlut DEN (a nwwsunbM atraunts apparad trcd.npd is the milk.
The Andinpa indiat.d that the Letatind mammary pland tratwnitNd the oueinoSens or
tMir nteeabeJita as toutrd pr.viouay, ffor the pl.eatta.
Moxrauo 111!): sriternie art.iooprr indua rspirstary tract wmon in varlous
animal species. Typial wmpte O( systsmit: Cutinobens ut the N-nitroso cornpounds.
which require n+wbotie conversion to aen tlurir areinopatie effect. In thit rrnew parr tiCYLr
nnlphatif i{ pYt on the comparative studies ptlfCflnad 10 the Ean1e tpe0et wFth.
diffestie/ nitronatiea, proridinjan apsrintnual nwdd in rhie! it is poasibk to sssminc
and omtetata the biodrc+ninl chanaa pt+oeJinS the deretopmatt o( dtxaetsbiR tunan and
tir areinadcnic dfea. ie addition, studia daaibinS rtilersistie or additin dfeev in
te spiratory orcinotenais arm rs.ie~.ad rtnd d:nu.rad. (Authors' abnr.et.)
Moe+rwao and Si.memt (1201: Four Fouptt of adult mak S).ian gofdca harmurs
tra+votf 12.eekly subeutaneous inj.ctiona of diethyfnitroasn+ine (DEM. each at the doae
o(s.0, 2A, 1.A and oJ rn4, nsp.airdr. The ttsatkad arcinopatie eQaa o( DEN on the
L,.r TR HN 0a"f' 2C"°..Jt ::..:..~ 6
/1
Chemieal Grt:inooftnaii in Syrian Hamuars 122
tespieatery enet wat eonArmed. In addition, the pe.aent rsults dearly demo+utnu a
poaitivt dole-r!lponft Correlilion for tumor induction 1/1 the upper 1tSlliralory tract
(nasal arities. larynt, and trachea). The ntoplattie response in the lo.er respirstory tract
(Eronehi, bronchioles, and alveoll) remained very low in sll four sapsrimenul rroups.
(Nota contrast with eQect of DBNA ottich ausa tunon of lowr nspiratory vaa.)
Nasal cavity tumors de.doped early and reacAed incidatas raryinS from 17 to !!%.
~t . Tbey indrd.d squamous oi11 papillomu, spuunout, adsao and anwpiastir areieomµ
a.dl as ateurospithelial tweoes. Tunwn of tM
lafyntt raacltsd inada+KS of 1!-?2%,
sAd tnetaa of Ota traehn ineidenoa of from U to 10t)%i larynt)eal and tneA.) tumors
ww tnosUr multiple polrpt and papiUoma. Tumaf in the ae+e bratchi .ve rva and
littoloSially similar tQ the tracheal tumors. Only thrs tumors of th. lung .wr+s observed
in a total of 142 animsb, and they had adenomstoatl uructura. tn add+tton, a fetr pai=!~
atal prolireradva kesiont aoa.rreti in the pulmonary Oaesnettpma.
TItK present results< dernonstrate that the ondnoSado respon~a of tAe Syrian Solda
hamster to DEN followt diuinet paterns for /ha diReeent asSrnenas of the respiratory
psum. (Authon' sbsuaet.)
Poua n d. (1401: The morpho(op of moptasnr in the nasal ofaetory region of the
Srrian golden hamster ottterv.d a(ur et lnjaaioaa ordirrpropytnitrotaminer bAydroay-
proprl+-propylnitroununs, boaopropy4wOroprlniuounwil, and nwthr{.apropylnitrp
famint 4R dl9lLTibtd; all (ouf ODASpollndi induced Wn1orL NaoplaSliC changes MaR
eharat:tviad by the prolifention of three often intermingled all tYpo (tarSt whoida),
cylindrical and small alq. Thee adhwent simibr to calls of olfactory Slandt, wsunt"yw
lar aJb and bwl calls. NevroSenic dema ta .ers not identilkd in the tumora TheesfonR
thesa neopiasnu were called carcinomas originating in the olfactory apthelium; the
diaSnottic aitvia were d'acvued.
Poua d.l. (142): 2Hrdro:ypropyl.n-propylnitrmamin. (2HPPNa, an arunrd
meta4olite of.di-npropY(nitrowmint+(DPN). Induod naoplalnr in tln raqveator, eystmn
of Syrian Soldea hamsters. The nasal cavity and tha traehn sne dte nria tarret orpeu,
but tumors .efs also found in the liver. TM tareinoSenic eRan of 2HPPN .tu onm.
qared to that of DPN and nrthrl-n-propytnitroaamins, another aswn.d esuboliu of
DPN.
Ptwa et .f. (1451: 2.2'-Dihy,fro>tydW.propy(nitroaanrna (DHPNI, an attwmed
etetaboliu of diarproprlnitronntina (DPN), injieted subauta+ra+Nr oao .+dlr for
fife, ws areinoSenio in Syrian hamturx. TM nnin urjet orssna ovt the respiratory
traet, pancreas, 6vsr. and kidneya. In tha tesoratory system the wdaz aR.eud wv+tienta
.vs the nassl w.iues snd the lunss. Ade>tomas and adeoeaareinanaa, masty of ducul
orifitt, sn induced in the pancreas. Lint neoptasntt .era heetanyoatdothdiomaa,
anpossreomai, hepatotellutar sdenomss, eAotansiomaa and Kidery
neoplasnr .are adenomas and adenowrcinomau The rnor9holoSy of thr Yduord aeo.
platnr wt deuribed. as sK as IAe arl.w d DHrN. eornar.d to tAat of snotAV oo.-
sibk metaboiits of DPH. 2hrOro+rypropyl w poprlnitrotamint RHPPN), t+rhiel itt
formed (n .ir wiUt only one aliphatie tdtain degraded ria boaidauon.
Pova .r d. (1431: weely wEcutaneau injanian of 2.l3-it1 md/kt body aeidltt
di-nropropylnitrrnamine (DPN) pwed papillary tumors and nreinomai o/ the rapintory
system in Syrian golden hamsurt. The trachea was the main tarSa ordan, tlwt the nasal
antw. IunSs., stem bronchi, and laryru. The number of tumon in the trachu .as the
.
aR
CTR H~`~ +42'~'~'~"7
Horsuac:rtt
124
largest in the upper eetime++t smaUer in the middle seSment. and smallest in the lower
segment. The IoW dow of DPN rvtulted in mostly benign tumore of epidrrmoid, muea
epidermoid, and poty"ta type anC a few squamous odt ardnotrvts in Ute anterior region
of the nasal avity. Wheros the highest doses induoed, in aildition, areinomu in the
posterior region of the nasoturpinsb and ethmoturhinab ht 7!X of the :nimah. Rautts
demonstrate that the eareine+aenie respane of the S» Oden haatuer to DPN fol.
lows d'stinst pstterrs in the diRerent tepnena of Ot. n:epirstay tnet.
Poua .r .L (I16): Weekly suleutaneous injeetions (12.3_ 23 and 50 mVkt body
weight) of math) l-n.propylnitrosamine (MPN) given foe life te Syrian golden homstm
aused tuerors V the nspiratory tset and liver. The main tarpet titsue ru the potterior
region of the nas.l avity - hsre adsnoarcinoma sre mat eommon. Papillomau rsn
found in the taryns, ertehea, and uem broneh7. Adenenta and areinomu of the lung
develeped mainly in females treated with the hiaAest dose. The mapholoay of the ob.
aerved ueoptasms and tM teetabolit: retation of MPN to d4nWopylnitronmine are di..
tamed.
T.se. er.l. (It)): Three thousand seven hundred normal appearin114m1eki of ten
tnClrcal papillomata.wA.-h hat: boen indutsd in Syrian golden hsnuters by DENA..ere
studied eytopholaneu+aQy. Atthouph the nueksi of the papittomata had almat the ssme
oontent of DNA u dod normal alb, they..re about twiae a)arSia. They *sre sli{Ntly
moes common in the hyperdiploid na,e. T1e erae eenesntntion of ths Feulaen.aained
DNA pe tweinr ir tA. r.pJlanata ra Otmroueosdty i.eeaas.d. Sinu7ar relationships
woae e0tained for the uMal aer.tent of twdeie atios and Aituaw. In addition, tAe linnr
eetressioa analysb d.ds.ed for the nueNi ef the pap'llomata a diminished eorrelation
between nuckar volume artd ee+stent of auehie acids or hista+ea. The importanee ol the
resutu is discussed in rqvd to OWntitati.L eytophotomeerie aituie of weoplasia. The
eh.dM it. Uw t+ucl.+r vWh.nR the widening in tM diw+Owion eurrs of the histograms,
and the daa+aw in t.r eor+.tatioa of nall Oarsmaers ars re*uded as eytophotonxtrie
epuivaksnu ot'wpe d malidnanry' M the tow apptiad by Roeat Rotttct (Authors'
abatraet.)
N'ymoaa and Hoenr.ww (Hf(: Eiphteut Inmsten (Syrian Goidsr4 LAtC. random) bred) at a time ars
wereced to :he rano+.e of 12 eiprettes p+lfad In the standard fashion
and remain in the 70-luer esposure thamber ler 15 etin. This Oreoadurs is repeated every
day eaeept on SaturJsye and Sundaya. The diwcsioe af Un rup'trswry ttaet s sinutar to
that tkscrihed for miea
In another aspvimental settinj, diethybtitroaanvee (DENA) .ru administered to
hannt¢rs by the suecveanaoun routs so u to paeneitiae tM nspintory system to the
eRaeu of e9prette smote. Initully. the eRaets of four divided doses of DENA injected on
alternate days were Kud.ed .fiat total dosn ot t. 2,1 ee S ms were Sivsn and e:powne
to lnake .1* beSun 10 days after the lau itljaetion. Aaimab erert killed when respiratory
diffi~euttiee or waaht lerb or kaR eeatrrsd. siVn that .as usually associated with the
appar.na of tunars wthe wspwstory traet.
In w6spuau sN+diei. Ywa found that a teoee statistially meaninifut method. as
well as a more prsasat oee. .ns to use a x t mp or a 0.! rnS ot DENA as a r.ensiusr.
All hams:atw the+t kille1 afw ti months. le this strain of h.nuurs, the h,pHer DENA
elo.e appear.d to be thi inorm sstitfactory for studying the entwrcing effect of a given
smoke envirptmcnt comitarsd to the eQeet of DENA atorw.
L..r TR HN 0`°y' 2-69C~ :u
Chwhfal Carcinoscnah in Snian Hanaten 123
Tracheal Instillation of Carcinotenic Agents
In the 18th Atomic Energy Symposium on Jnhalation Carcinogenesis,
MoxrrsArro et ol. (122J reviewed their methods, especially intratracheal
instillation of particlebonded carcinogen crystals, to induce respiratory
tract carcinomas in Syrian harnsters, and in the Atomic Energy Commission
Symposium 21, SA.norn (ISIJ reviewed the histopathology of tbe induced
tumors. Fcnon er al. (3aJ reported more recently that rerric oxide was not
necessary for the carcinogenic effect of intratracheal BP instillatiotts to take
place in a dose-related fashion, an observation contradicting that of Kus[tt-
trat 1961, who, in 1968. reported that BP alcne:nst+U.d into hamster trseba:
did not cause cancer. The most recent study of this subject is that of KouAra
sxt (92), who, in 1975, reported that instillation of BP alone (weekly,l m j in
saline for 30 weeks) caused respiratory tumors in about 50% of his hamsters.
Satttasat er al. (163) noted that BP in combination with ferric oxide caused
` squamous metaplasia in trachea and large bronchi of hamsters; on the
contrary, rats developed squamous cell nodules of bronchialveolar origin.
Htt.ialcH et al. (70) further confirmed the dose-trcspoase rclatioasbip
of an intratracheally instilled BP suspension to the number of tracheal and
pulmonary tumors produced in hamsters.
HAatus rr ol. 1611 later described the acute ultrastructural effects of BP
and ferric oxide and NM U on the hamster trtubeobronchial epithelium, and
SAsrtorrt er al. 11611 studied the effects of different numbers of administq-
tions of BP in ferric oxide. HAttnts Or d. (37J also reported on the autor»dioo-
jraphic loalirstion of bound and unbound'H-BP in tracheal epithelial cells.
Related studies using tracheal insutflatioo of'H-BP with arbon black or
asbestos were done by Russian authors, who showed an increased macro-
phage response to administration of these mixtures as compared with'H-BP
alone (I $0). KEr+tvwtt and Ltrns (SQJ used radioautoIIr.phs for localization
of carcinogens in lung tissue,
All of these studies demonstrated the potentiation of the effects of BP
(whether inflammatory or carcinogenic) by its having been introduced into
the respiratory tract bound to a particulate arrier. The most recent studies
by HcnttY et al. (6SJ emphasize the necessity for high tumor yield of the
physical attachment of BP to carrier dust. According to Stwuunuut et al.
,(167J, an increue of the BP/fcrric oxide ratio beyond 1:1 does not affect
the results.
In the haads of Gttosssar+ e1 al. (S1J and Lrtrtt et al. (109), hamsters
have been found to be susceptible to lung cancer induction by "Po inst,lled
r
i._N TR i f N 0'"'Y' 2[°"~A 99
I
How.uaca
/ \
126
into the trachea in saline or bound to fetric oxide. (In this ase, it appeared
that radiation was more carcinogenic when uniformly distributed throuEhout
the lung. i.e., essanating from polonium in saline rather than that attached
to ferric oxide arrier.) These authors also oonbrmed the arcinogenic
potency of BP in tracheal instillation and recommended hamsters as a good
model for the study of interactions between radiation and chemical agents
in mpiratory arcinolenais (110). The same investigators also noted that
marked differences occurred among inbred struins of'Syrian hamsters in
their tolerance of trachal instillations to uPo as well as the times of latency
for tumor induction, whereas the final tumor incidences were similar in the
four strains tested (10lj. Other straindcpendeet variations of susceptibility
were noted by L.Atzson et aL (99) for viral aranoVnesis.
Intratracheal instillation of otber potential carcinogens or cocarcinogens
(some of which might be contained in cigarette smoke) in combinition with
ferric oxide was studied for DMBA (179j. DBP (I60). 7Hdibcnso(c,g)-
arbuole (16a) and furfural (37J, as well as DENA (39J and NMU (59).
DMBA. DBP. DENA, NMU and dibenz.oarba:ok torned out to be potent
arcinoSens; furfurnl was not arcino=enic in italf, but acted as cocarcinogen
for BP, and DENA as well as BP were potentiated by ferric oxide.
In low doses, DENA was found to be ooarciAosenic for BI' in ferric
oxide (121). DMN, on the other hand, evfs by s.c. iajection, did not cause
mpiratory tumors, even when fetric oxide was btstilled into the trachea of
DMN-trated hamsters (17ij. CoarcinoSeaic elfeas in the intratracheal
instillation system (using BP as Initiator) were also noted with lad oxide
(9d), and with ttmospheric dusts (139J.
Quite obviously, the tracAeobronchial epithelium of the Syrian hamster,
when exposed to arcinopns and/or coatYinojens under appropriate con
ditions, presents a good experimental model for epidermoid ancrr of the
respiratory system. As such, it will be used increasinSly for fundamental
studies on the mechanisnu of respiratory arcissoSenesis.
K xtmtxt+.r ol. (NL making an intensive study of the cRects of vitamin A
deAciency on the behavior of trt{dseal epithelium /n vlrro, found diRerent
electrophoretic patterns of RNA in the ddlcient epithelial cells, a phenomenon
which is reversed by addition of vitamin A. The same group also observed
Ls.lro that while the squamous metaplasias induced by vitamin A deficiency
and that induced by BP instillation are similar under the Gght microscope,
their fine structures differ in many respects (573.
HaRats er el. (59j noted similarities in ultrastruetural changes in the
hyperplasia and dysplasis induced by BPferric oxide treatment and instilla
Lr f K i IN 042700
I
Chemwl Greinoanes's in Syrian Hannaxe 127
tion of NMU. These changes were similar to those seen in human lung
tumors. There were morphological diffetcnces between these changes and
those seen in the epithelium during vitamin A deSciency. The studies of
Rs.zNtK-SCHiit.t.ttt and Moor< (153, 1S4J, Rrzr+uc-ScHGu,[n et a!. (13S] and
PottT et a!. (137] on the fine structure of tracheal epithelium durinj BP
nrcino6enesis are generally in accord with those of HAttus et ot. (SS-39,
61, 62j.
Most recently. HAatus 9101. (S6] described interestin6 abnorrnalities of
cillary morphology in the bronchial mucosa of hamsters treated with either
NMU or BP plus ferric oxide, which ccrresponded to those reepcrted by
others ir. patiects with broncho=enic carcinoma, and PoRT et d. (137]
reported similar observations made on the scanning electron microscope.
In contrast to these observations are those of STtut;s and Ftxow (1E2], who
did not 8nd squamous epithelium in tumors induced in hamsters by tracheal
instillation of DENA.
Sttwttlctt (177] made a morphologic study of respiratory tumors iw
duced by tracheal instillation. The studies of Urrtorrt tr al. (160] on vitatninA
supplementation su jgested that vitamin A might inhibit the respiratory oo-
carcinoSenesis of BP in ferric oxide. RoGms et ol. (1S6], at Massachusetts
Institute ot Technology, developed a semisynthetic diet suitable for study
of the eRea of this vitamin on respiratory arcinolenesis, and they pro-
aeded to investigate this problem with results directly contradictory to those
of Urrnorn with vitamin A seemingly acting as a cocarciaojen, as it had
been found to act in the cheek pouch by Ltvu and Pot.wcs: (103) (cited
above).
Gauctu tr al. (49] used the BP instillation system to demonstrate the
etlcctiveness of a rabbit anti-hamster lung serum in preventing induced lung
cancer.
Various methodologies were worked out to be applied to the respiratory
arcinorenesis system, using BP instillation into the trachea. Hu.tatcn et al.
(69j de.ised a simple method to collect bronchial secretion. SCtitanltElt et aJ.
(165, 166) devised methods for eafoliative cytology during respiratory ar-
cinoQenesis that proved sensitive and accurate. HAaus et 81. (601 devised a
method using colchicine to arrest mitosis for measurements of mitotic indices
in vitamin A-defuient hamsters. KaunuH et at. 1961 frew isolated hamster
trachns in organ cultures, isolated DNA from such cultures, and found
that in the presence of eritiated BP the carcinogen was bound to the tracheal
DNA. KAUrruN er 91. (ES] subsequently observed increased binding of BaP
to DNA in the trachea of vitamin A-deficient hamsters and in certain inbred
C"m IIN 042 -~01
i
Horttnca
128
lines of hamsters (specificaily. the BIO 13.161ine, showrr by BtttNFt>.a rr o4
(13j to be more susceptible to Jarynteal anar inductioo by aprette smoke
than other lines tested). "
Fnow ()7J: Thne groups of young adult Syrian kanrters, sicA consisting or 7s
males and 33 remales, received lf ..eky intntrt,chd iwillatimtt of furrural. bea:o(a)py.
esne (1P) and !P + rurrursl, respectively. The control RouM whiM eauicud of ls maln,
t.ceirsd 0.9% Na:I solution butwu otherwise similarly tr.ued. For aorne interim inror
nution, 3 males from the control group and 3 malee and 3 remaMt from eadt of theother
groups ..rt killed and autopried at .eek 30. The apviarnt was ternunated after
78 ..etu.
AP alone (suspended in 0.9% Naa solution) Ieduettd respiratory tomors in 41 out
or the 62 hamsters esamined Squamous ezJl attinoma of the tradtea was the most
lreaquent type or tumor observed.
fn comparison with trestment with IP alone, IntrstruAeal insullation of 1!P + fur.
lurat resulted in earlier developn+ent or ertaplastie elunga of the trschsobroncAial
epithelium, a Moner taunt period for trseheobronchlal tumors, and a few more bronchial
and peripheral squamous eeJl cueinomu. TUw tsultu suggst a arcaedno~enie dTect of
/urfutal oe the espiratory tr.et of lunstees.
Peritnehsl tuuoomu .+n observed i. 2 haenars (3%) t+aad witA !P alaee. An
aupwttiea eRat e{r furrursl en tJr htduatios el oerilnd.a! atLtotoan .u apperent
rreen the fairly lugh i.eidenar o(Nea tumon (p)%) emasrin5 is tt+. Qoup tratead with
sP + rwrttMl.
?Irre was no indiotioe that rurfurttl par+etses errdnorenie aeti.itr ol in o.IL
Ftaow er.f. (311: A positive dowr.epotw tdatlomhio abts for the induction of
rspiratory trset tumon In Srrian hamsters by the etprpd irtillation into the trachea
or partida or !P wapended in o.97i wa eotutioa Fa thi, retrie eaide ponKka aro
not indiepetrabit, although tAe rtent Felod wat 1oeger for i>aett.t.n t.aiv +na tee )P
particMl alooe.
. Faow er .I. (79J: A total ol 37 tumors of tlse lower trpintary tract (bronchi.
bronchioli and alveoli) was observed in 0 a+aM and reanale Syriae golden hanuten rol-
1o.dnS 15 weekly intrstrschpl ineulLtioet of DENA alone. The number of tumors in
this segment of the respiratory tystemwas 3 tinm higher MKa lerio oside was adminis .
uend simultaneously with DENA (107 neoplast7r is a total of 62 aaimaY esamioed). The
neoplactie response or the lo.a respiratory tnet mainly opniued of adenonus in the
bronehioolveolar ropon, although bronchial papillomee and a re.r peripheral aronomu
wers also observed.
The wtJlkno.t% marked ortinoSatio ed.et of DENA eM1 Me upper respiratory tract
of the Syrian golden hamue.was conrie+ned.
Gas.oat or of. 1491: This study was deaiprd to investigate the effects of pne++motosie
unti.AuwtHr lung serum on Ue ineida+oe or ehemieally induead hametsr lung earov.
Anti.A.mtttr lung wwn was produoed in rabbits by injeetiions at 1vdar intervals of
200 mg of boewpt:usd hensur lun{ tissue suspended in 1.0 mi of Freund't complcte
adjur.nt. Antieervrn was collected 14 days after the booster injection. Anubody apmu
hamster urum was produad s;imilary. Speci/faty or the fers w checked. Lung canar
was induced ie d! 11-...i old Syrian Iwroterf by 10.+eky inv.trachesl iroultauoru of
i..r f f'ti. HN ti..4 ""f' 2702
/ r
Gromial Careinose+wis in Sprian Hamsters 129
01 ml ef a suspentioe of bentsc-pyrene tnd hematite in nline. Si:teen hamstai recsived
an iitraperitonal injetxion of 0.2 ml of anti-hamster lung serum after each instillation;
14 naived 0.2 ml of anti.hamster serum after aeh instillation; and I S urred at unireated
oontrolt. All animals wen killed after I year. Of the 16 hamsters treated wth anti
lrntster lung serum, only I was found to have lung anar, whereas :n the t.o control
groups I of 13 and 7 of la hanuten, respectively, desloped bronchopene arc+noma
(Dco).03).
. Gaoas+r.w er.f. (31): Two Sroups ef i0 Syrian hamuas wan y.eo 11 .sk)y )arr
ttscfial insuiilations ef 0.2 and 0.01 yCi I'?o adsorbed onto 3 mS fertit eude arner
ptutido (!1% <0.75 Y) suspended in aaline, talcvlated to Sive lilnirne dossa af 6.700
aad 22S r.d to the whok Iuna. llronehoanic areinomau were obterved in 01 aed 43%
nspeetively of the hamsten in these two Sroups; nran induction uM-. .en 33 and
34 waeki. No lung tumon ha.e ennured in ariee;H ptj.ned wda:, Ve,O, p.rodn a1m,e.
...rout Qoupa or 30 hamnen vae gi.ea aparate intrnaaclwl hwitlauerr on she
Arst aed third day ef saeh week for 7 weeka. These groups received (1) 3 rrIll Fe,O, fot/o.ed
by 0.2 pCi "7o alone (is aalloq; (2) aline followed by 0.2 nCi "7o alasr (I) W°ae
followed by 0.2 t+Ci "`Po dQsorbw) v.no 7 rM Fe,O. ond (4) txline followed by 0.2 uCi
$'Po adsorbed onto 0J m{ Fa,O. Raulu thus far for perant survivon at 11 weekaand
number of anirtuts with bronehoteniu tanoess by 27 wetks tfter the Mt inpetion am
saspenirsly; (1) 2% eli.e, 17 tuason; (2) 6% alive. 9 tumors; (3) 21% alive. 7 teewrs;
(4) 32% alive, 3 tumera. Preliminary autondioSraphio etudia indiate that NPo ad-
minbter.d adsorbed onto Fe,O, rsrnained Metly useeiaud with visible F.A, t+Ltida
in the lun6s. and its deposition was nonunireern depending on that or Itie panielea 4"Po
administered alone in sal,ne, however, was distributed hotnop:nously throueAwt the IveS
parseuhyma. These radu tue6est that under thess eonditiorr of eapoeun s-nr:ution
may be more arsino{enio when it ia nore atiformFy distribus.d dvoWhort the lung.
(Authors' abunet)
H.uue .r.l. (S3J: In ae anirrrl snedel, 10 Maratr.chal (I.t.) mrtilYSiar e1 sislrt
be (a)pm+te (DP)-Fe,O, (S m6 ads, 3 tiar/wak) x N-ntethyl.Naitrot+ar.s (HMU)
(0.5 ms, w.ekly) ausa sQuamats odl areinoyna in the tracheobrascbd epUdimL
Hamsurs are ssrially saenAoed and the rspiratory traet studied by sMevae rrrcrampy.
The morphopcnau of squamous coil areinoma Y eimilar with either are,eeOeR Our
curtent dan are consistent with the hypetheain thss basal os0 hypvpiasra p.aedeti
squamous rnwplasia (SMP), which Is followed by spuamov: n.oplasia. SMP swe,d by
these arsino{ens an be dittin6uislyd from SMP found during vitam,. A-ddlcserxy
(Adef). Enlarped nut:iei iedented by rytoptaamie istq{inalioro /+leonterphs a,eleoii
and defeets in the bareaneat tnembraee are ratriasd to areinopen.indusad SMP. The
tumons aaed by eithsr NMU or DP are similar ht uhrutrunure to aomstv.bY bunar
tumors of the luns. Quantitative autoradio6raphy an determine the Iuakrauea of H'OP
and H'NMU in epithelul cells, when isotat.d tstAeas are incrbatad a..n..+u tlKSe
ardno6enc /a rrre ).t. aposwe to HI-NMU tauties labeling of Irschsal eptLeliul alb
by 2 h. In .t.e studies using H'-!P given to normal and Adef. hamsten .re at propev
to determme it areas of SMP meubolus and bind'H-OP to a pnur ata+t tiua .ormal
respiratory epithelium.
H..aa 9181. (S6): Ciliated cells ars an integral pan of the mue9tss+4ary ennepen
eyuen4 which serves as a defense apinst inhaled partlcu4ta as well as noawus csesn,eal
f..r wI 1'!a Hi 3 042703
/1
\.
1
Horauacat
130
and mierobial apenu. This system of dcfenst an be damaged by some of these no.ious
for Aivision, first in basal and then in all layers of the abnormal squamous n+neptasiic
ttpithdium. Defects in the basement lamina wero found in lquamous meuplastic les+ons.
The ultrutruetunl e#antss in the useMobronchiai epiU+slium ..n similar to those 1
described in hamuen esposed to BPderrie oaide as well as to those described in unoWpa
do¢ and ia human bronchotienie etusinoma. The sWuamous metaplauic chanpta induaid
apenu and underso sQuamous metaptuia. Ansar and GN.ouur have r.omtly describlq
some interesting abnormalities ofeiliary morphology in the brond+ial mueoa ora patient
with bronehopnic arcinoma. we dacribe similar abnormalities in the tracheobronchial
epithelium of the Syrian golden hamster followinj intratraeheal inftil4tiotu of arcinotenie
riiiman of either N-methylN-nitrosoura or benm(a)pynneFe,O.
H.ai d er el. (f7(; Tl+c intratrschytl instillation of beruo(a)pyrsne (BP).Fe,O, in the
Ssriri. golden h[mster aused a sumt::r of changes in euetar strueture. A sekuive in-
einr: in the vowaetional am of nuclei of basal eellt was obtsrwd in multipte focal
areas in the tracheal epitheliue. This ine.aw rtprasemed an enlaryement in the aou-
saaionel am of eudtromatin and a dispersion of the hetaoehromatie.
In shon-tene organ cvlture of traehea, incubation with 1P'H caused labelin6 of
euclar and crytoplasmie site in tnucots, baal, and eiliated odls. Quantitative li{ht
mieroteopie autondiopraphy revealed that prior !R .t.e administration of unlabeled BP
caused a subwpuent increase in the in Nn+ binding of BP'H to epthelial alls. The total
binding of DP-'H to epithelial calls was inhibited either by the addition of 7,11-bentoflavone
to the incubation medium or by ineubetion at 0'. These raulu suggest that enzymatic
activation of BP must oaw before BP can be bound. The nuclear loalintion of BP.'H
ra primarily in the hetaod+romatin, as detarrnined by ebetron microscopic autoradi.
oaaphy.
H.atts et d. (S1J: An aperimaual modd which oanp.ras closely with squamous
adl ardnema o(tle hsnB in tua is being studied. Syrian golden damsurs aee treaud with
multiple irotillations of either bento(a)prrens (BP), adsorbed on ferric ozide, or N-nxthyl-
nitrasourea (NMU). After treatment, the animals am witlly killed and tAes nsspiratory
tracts are esamined by hiph-rasolutien light and deetreu microscopy. Sipnifkant ultra
ttnKttrsl hsions which am not seen in the squarnots metaplasia found during vnumin A
deficiency are found in the.quaa,otr metaplaw caused by these artanopcns. Ultrastruc-
tural alterations in nuebr urueturo and de(e:ts in the baement membrane are restricted
to the puamou metoplasia au.ed by either BPFeA, ttr NMU. The ultrastrueture of
eepierinrnully induced tumor db s similar to that fotnd ia hunun tumors. Studw on
the effeet of high doses of vitamin A on the Astogerrs of tquamotr aU carcinoma ut
the Syrian golden hsmaar are in progress.
H.naa .r .l. (!9): Ten intntraehal inuillations of NeKthyl-nitrosoura (NM U)
caused squattaus metaplastie and neoplutie changes in the traeheobrone)tlal epithclium.
Abnormal tquemous mctaplauie eNb contained enlaryad twNei deoply indented by
cytoplasmie invaginationro. pieomorphio nur:koi4 Namentous Iranula and nuny eyto-
plasmie fihrils. Prior to the appearana of tumors, aetoradiopranti revaled cells prep3rma
[--r i m R MN 0'"°9" 27ti...+'.°Y'
C]temiesl Carcinocenais in Syrian Hamsters 131
i
I
iadeu in vitstnin A4eRcient hanuters, we determined the dest of eokAiciee, whieh arresed
the rnasimal number of mitocic cells in mciaphnse. This dose of eolchiane was 10 mt'kt
in the esophaleal epitheliurn, 100 mglkg in the duodenal epthelium, and 300 mjika in
' the re{enerfung epithelium of the trachea. The temitivity to colchieine was, eherefore,
~ .
i
organ dependent. The number of mitotic cclls arresteJ by colchicine was increased in the
tratdtul epithetium of vitamin A-deficient hamst.rs. Incorporation of'H-thymidin. iuuo
trwcow and bsal jeeus was also aup+xnted and measured by autoradio{nphr.
Haua N d. 161): 7Ae pathojenetus otepithelial byper9iasia and aouamo,o mera-
Pitsia of the tnolheobronchial epitheliun4 induad by polynudeat 6ydraiarboti, aaa
ttudied, w{th the Syrian golden hamster as a suitable animal aadel. Tte aana eNlulat
elaanda in the traelKobronchial epithetium, produad by intratraetrsl imtiuatierr of
ben:a(a)pyrene carried by lerric oaide panicla, indutMd foal replaotmatt of tbe oolun~
Yr tslts with pteomorphic cells. Tfiefe bad Sbe ultrauructural features of atypial,ai;moutc alh
i.. tytepluT .:damcnts. widensd interortlulorapaoa abnort+W deemotomo,
and increased number of lysosonul derivativn. Polylobulated nueki and ohotnorobic
twcleoli were prominent Ifndinp after multiple bntillationa of ben=o(a)pyrana:ferrie
osi0c. imrseheal instillations of ferrie oxide alone or oyreneaarrie otide Oroduad
besal oelf hypsrplasia, whieh an re.enible. Tht atypical atlusmous telb i+duad by
ben:o(a)pyrenti-fenic oxide had uttra:tructural festurss similar to byperplapie opthelial
alls described in the bronchi of snakint dop anJ neoplastie spuonroue otslb described in
human bronchollenlc areinoma. This investiption ie one of a win of audisa to elarUy
the histopnesis of squamoua csll eareinorna of tbe lun=. (Authors.' abtxraa.)
Hw.r and KAunr.M (6)): The persistena of bana(a)pyrene (CP) in the rapiratory
eraet of hamsters was determined after intrsararlrsl instillation of the particulate duua
arbon, vuminium oaide, aad ferrie oxide (in the four ws ranges 0.3-1, 2-3. 5-10, and
1S-70 t,), each e:oued with DP. lk+nuae the 2% dusa2!L aroinodat peparatioru wan
prepared on a weight bws, density difieretuae rspuirsd that nrore particles of arbon thu+
of aluminium oxide or ferrie oxide be divan. Analysis of the DP content of haerta iunga
ima+odiately after inuiWtie. tibowed that tha earlon pepaqtiom contained rnore ar-
ranopm 8P was cleared much more slowly from lunp ot arbon-treaud aninui:ti and
Mere was potiti.e cnrrelation between partitie aiae and raentios rate. The particles of
aluminium oxide and ferric oxide retarded the tiearana of (he aranopen, but tt!untion
nta did not eorrebu with particle siu. Theae raulu wra dNettsscd in relation to sbe
patAoaenesa of lung csnoer In hamsten trpttd by intntrseRql iroWlatioM.
Hn+ar er d. 164): IP, prepared as a colloid auspenaion of Ane p.nicle in 0.5%
Wclatin-0.9Y. NaO nolution, was administered by inustraehral insti11.4uon to 30 nuk anJ
30 fenule Syrian golden hametert The control QouO, whicb ea*uaed of 23 makta and
25 females, rsoeived 0.5% pelatin-0.9% NsCI soluuon. The batru+sn were treaud ..ekfy
for i waeks and reaived a total don of )11 mp of IlP. )P induad respirsbry tumon in
26 of the 63 hanutert; eumined. These tumors incb+ded ptan.aa acU and anaplutic
arcinomas, adenoearcinoeut, 6broaareornaa, adesonras, polyp. and papillornas. Each
aetnKnt of the rsspiratory traet, with the aception of the bronchi, had a similar ineidenoe
of tumort Oniy twa tumors were diagnosed in the bronchial region. Of 17 control ham-
ueri.
I animal carried a trachnl polyp. Rate of clearance of BP from lung aha a ainble
administration was dependent on the doae of areinopen. Low Joses of LP rpe eleared
rapidly, while the veckly dost instilleJ in thu study waa rtuineJ for a long time.
CTR IMIN 04*2-'705
C
H'WBUacat
132
Hswnr er a!. (63): Three mi:tures of bento(a)pyrsne (8P) and ferric o:ide wlth dir-
krcnt ph)sinl propenitx wsre pren intratraMeallr to Syrtian Solden hamsten (or an
sxamination of their neoplastic potential. Hatrottas trattd with a pnparation eontainin6
large auretata of BP and ferrio oaide oesulting from nucleation of 8P on the panicks
shoMSd an earlier onsst and hither intadenam of tsapirstory tract tumon than anima)s
Sirln a etixturr fonetini~L smaller rV.esstc preparsd ll~ oond.jrindint. The paust
aw..ta of tumqt: r. paan in th,, tr.eh:, cnd tAe p.,,dominant type was the sqw
mous ei.rcinotnr.. A ti.ird pr6p.ti tion in which tia earatsosen wa not attached to the
ferrie oxide showtd a low tumor ineidena similar to that tar.sent after intntrachea) in.
tubmion or 8P in 6etrtin without a carrier particle. For Ma model system of mptrotory
earttinopneua, the phytieal utaeMtent of HP aad the earrier dust iu neoessary for a luSh
tumor yield.
Htt,nteM ar d. (69j: After btdtteing lung tumoy with NmethylNnitrosourq
(intrstraeheally) and dibutylnitroasmirta (subcutaneoutly) in the Syrian golden hamster,
a simple nset.hod Was devised (or collecting brondtial saeretions. The raults of the eyto-
loSieal and histological investiption ara daaibed.
HntacH er.t. (70): The induced tracheal and lung tumors of Syrwn golden han.
aters resulting fro+e intratraehri1 instillationa of diRersnt doses of benso(a)pyrene (0.1-
9.77 mg inerrasin< <eomnriatly with a factor or 2.3) suspended in a new dtstKnm6 agent
an desesibed. The results dentorouatt that eriN.+tkly appliation of 0.25 and 0.63 mg BP
and with a wrvival of more than 30 a 11 weNta, snpaaivelr. the highest tumor tata of
SO'/. fa tJts atst:Asa and 30% for tba /unp ws rtalised In each of tNese two dou6,
Iroupa.
Kaa.uM er .l. (N(: The e1.Rrophoretie pattern of RNA molaeulea that aro .yn.
thesirsd in riaa in traehpl epithe)ium from hamtteN deP.eient in .itunin.A di/Jen from
that of RNA trynthsie in nccm:4 nirdod eaurol harmtera. There ii ias RNA of low
daarophastic mobility In the epithdial alb defiwnt in viumitt A. This altereuoe ia
t++esrrd after tlta deRciau arAimah have baets trated with .itamie A.
Katnw.w.r.f. (t$]: An !a .tnm drort-term Lattsue ertte}tsr,l organ evttun system
has baen studied in an effort to de.dop an ar,aay systetn capable of identifying in vi.e
petet of incrosed susaeptibility to respiratory arcinopan. Tracheas incubated jn nne
in medium oontainin= uuistad bestm(a)pysa+s (8aP'H) have 8aP'H bound to the DNA
atrataaA from the tracheal epithelial oeW, then purilbd and banded in 00 jrsdients.
Prior intretrachal ttsatman of hamNen with 8aP plus Fe,O% ia .iw resulted in enhanced
in .ina binding of 8aP'H to tracheal DNA. This enhanced binding is inhibited by rncuba-
tion in the peesenae of 7,i.bwuofia.otr. INneubation at 0 reduced binding to a greater
satent than 7,11-bensoflavone; these tsulu wtriu that binding may be composed of two
eamponatts, a+a inhibitable by 0 eeatperatuna but not by 7,1-benwAavone, whaeu
ths inducible eempotwtt aptsears canpletelr inhibiubls by 7,FbensoNavons. Then wu
iaaeawd binding obterr.d in the utehna of witantia Ade6eient Itamsten and in esriain
inbred hamfser strains. Fwthermora tlrre appesn to be an invsrss rsluionship betwen
hanuter a6e and indutable binding tevels. The qwstion o(whether thae results are predic
uve of the sute of tuntsptibi)itr to wpiratory arasopnsis is being studied by com-
parabk long-tsrm evano(tenew testa.
KAuti.w .r a!. (16): Isolated uatbess ..re iaeubated ir. .iuro in the praena of
tritiated benso(a)pyrate. Highly puri6ed DNA tru isolated from the epitlteLal cslls of
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CAemial Careinopenait in Syrian Hamsters 133
tbae traeMu and rrat found to contain bound'R'H. If Iradtnt we obtained frorn
hanuten previously treated intratrachcally with bento(a)pyrene plus Fe,Ob this binding
was eahanoed. Inwbation of erael~eat in the ptescnoc of 7,i-benaoAavone or at a tempera.
ture of 0 resulud in inhibition of this enhanad binding. Thse raulu tuggat that the
aschnJ epithelium is able to metaboiize ben:o(a)pyrens and this e+etatlolum is tsocasary
for tAe inducible binding of benio(alpyrene to DNA in (Au taua<
Koioatet er .t. lt7): We deeribed Iory-tarn t+urviral of abeuurrou afcbeal
ltfespianu in rau, mia, and hamsters. Inul)ktioe of earooopetie polyeyclic lydreearlar
bte.tablithed rat tredtal grefu resulted in the dsrelodmau of hypeylauaw dy:plaai.,
aad apuamar tneuptt}w within 4-7 days. Si+nilar tpthdital ti+anps .ee. abo induesd
witJt taSamte ae+oke oondentau. In one tnudy, u.hici h uili in program. ie.ui.e aqur
eaw eell eueinanu deve:oped in 7 of 13 traeiw.l Sra/1s betwm 2i and 35 .+elu after
imtiliatioe of S mS of either 3-mmhykholantAtsne er benro(a)pyeene. No turnon lr.r
at yet appeand in the ttrsfu receiving 1 tns of N-nitraomethylur.a. Tse uefrtnt.e o(
this esp.rintetnal model for tnorphoSerwis and sa>r»rdimioveetah studio is ditntwd.
Ko..restn (l2J: Rspiratory tumot induaion, w tatsd fx the tumoripenie.eWity
af bsato(a)pf~rerc alone. A peup of 72 mak and 28 faneie Syrian golden hanrtets.at
Siven w.ekiy intratrac)ra1 int;tilbt)oo of I e+g of bsnto(a)pytene wstxnded in itotonie
asline, for 30 wslss. Squamous eell eardaorn., adsnoareinonta, anattiutie uronortr,
adenomt, papiUomt, and polypt were indund Ie eM tapintory ttfet of haart<rs. Tunot
btddenm .en 12.3/% in males and 17.7/% in fermleL Rapiratory nrdnomaa .vt:
inducibk in hamsters by simple instillation or a low dote of batm(a)plRVr without t.inS
a tauface-aetire agent or esrrier dust. Thee Andinp may be useful as tundard data for
oowsieopatsis audia whm using ot)w modalitiet ootnhimd with benso(alpyrme Ie
aperimenul studies.
Kon.rAswt and Oe.roro (91): Ie 10 weekly letratr.eMal injatioae, fear groupe of
fyrian boldeo hamuess .m jisa a arpeesiea (ia itoeoeie aiine plus 0.7% arboey-
met)tykcuuloa aoluuoe) of h.d oaids (PbO), bataa(a)p)meee (OP) nraad with PbO. ItR.
or control vehicSe, respeeti.ely. Another poup.ru kept aa an untreated eentrol. Atrpieal
epithsiial proldentiont. adenonuu, and an ad~oo>t~noet; wers obwwd in the lunp
of hamuen psn DP mia.d with PbO.wtr.u no tunrorots t9sanle srs found in the
etAer pouptr These aeoplastie tltanps otiSian.d naMy, iis ths broeduo.lsolar am.
tb0 alone ieduc.d byperplsuic and puameu tnwptutie fao or the at.eoiar .ra.
T6a+e essuiu tupswd a mtaronopatio tsR.a of POO.
Kaaon:t< (9q: The term 'tauts' el lung tanor hdiotr teuitipiiory. This tlia
eue+ion .,ll t:onoera iwJf with se.ersl tupav of ousation u i0unrnaad by atem rintienu
tioa !n orde. te avoid any misundert<uadinS I ahould like to aute eey anr.cuat at tM
outset that the tin{1e tnott imponaet aux of lung eanae is tnaa s opntte mwhag.
We a+ay nevertheless properly ask how iw+p onoet it productad. Muttilaaoral ousatioa
4 eo.r accepted for alt diseases. I tAall tat t>iscusi eoeatitutiott.l and/ar Senetic faeurrs.
In lung esaeet, tiwe most impe,rtaw detatnisastu of .Itaek ntm mq aarf fros adt
urnne dtaractsrstin as pnK+K instabiiitr, and henoe ausorptibdity to sonvtuc tswtatioe,
to rather mundane difTercaee ia tAs angle of bnneJtinS of b.ot,+ch4 txoduang ra»uons
in t8e amouat of impinlement of inAakd p.nievlatea.
Lfrfl,l et.l. /10i1: The nsponts was studied or rouf inbred strains of syriaa barn.
tttxs to muitipk intratracheal inuillatioru of the alpha emitunj radwnucLde "Po ab.
C T R M N 0 42 7 0`1'r*"
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sorbed onto hematite panicles. Marled differenoes occurred among strains in their.
tokrance to the instillations. There al;o apt><ar*d to be sipi/kant diRennca in the tumor
induction tims, but the frepuency of lung tumors waf timilar in the four strains - varying
bet,Aten 33 and S0!:. The m/luence of genetic strain might wsJl be more marked with
chemical arcinopcns in which meehanisms of aaivation or desoaiBation become impor
tant factors which come Y.1der pnetif: control.
L+rnt el.l. (109J: 'PO was absorbed onto ferric o.ide pankles (9i'n <0.75 u
diameter), suspended in 0.2 ml of saline, and injaud imntraelwlly into Syrian golden
hamsters. Groups of 60 hamstsrs wcre aiven ti vwskly injatans.of either 3 mp Fe,O,
alone, 3 ms Fe,O, 0.01 yG s"Po, or 7 mg Ft,O, + 2 t+Ci s'Po.Thas aposures aere
euimatad to deliver 0.225 and 4.300 rad, respectively, to the whole lunp by the end of
the Ant year. An addi.ional 200 untrested hamsters were kept u colony controls. All
hamsten .ere followed for their lifetime and autopciad after dnth.
In the high rtdiation group, the first lung anar appeared 13 weeks after the Rrst
injection, anc only 9 amnub were alive by the 43rd week. Of tNe 26 hamuen which died
and were autopsied dunns the ISih to 43rd weeks. 21 (II1 %) had sinale or multiple bron-
ehot;enic wmon, and 4 more ,howed areas of bronchial epithelial hyperplasia and atypu.
The tumors wese all nrs.d adcno and squamous cell arcinomas arising from the bronchi
and terminal bronchqla. Only onr deRnita turnor has occurred as yet in tbe low radiauon
group. but 4 of 3 hamrte+s dysng during th6 13th to 43rd weeks showed arsat of bronchial
epU+elial hyperptasia and atypia. "b such tJtanp and no wmorf ha.e ooeurred In the
unirradiated anmaY. Ia aeethar, pgroup of 170 hamsters treated similarly to the high radia
tion group above, daMM keor~bul osnats Savt, thus far oesurrsd ia S ban>aten which
died within 23 wcJfa af tae 6M utpcticn.
The na:nv%r 'epcan to " a2ttitive,to & induction of beenehosa+ie carcinoma by
'Po, and this model m» be useful for attrdyin{ lung asron induction by a-radiation at
the dose levels found with roees human eipawre. (Awhon' abstract.)
Lsnu and OToou ;110): A hiSh iecid~sna of nupiratory enar has been induced
in Syrian golden hamsun by repesud IntraUad+sl inetillatiooe of either bsruo(a)pytern
o. "Po adsorbed onto he+evuu carrier prtickstL botA the tumor ineidenoc and the mean
induction time v.ere related to the doee o(areieoten. Dento(a)pyrene induced a spectrum
of wmors, amonF which the type oawring moet trspuently wers epidermoid carcinomas
of the trachea or maw bronchi. °Po-induad twmora sn almost eaduswsly combined
epidermoid and adenoarcinomas that arose perit>>+sratly; these tumora oavrred in 94%
of aninuls in the highest eapowre group. Htunuen apprar panicu4rly sspoeptibk to the
induction of lung anots by aradiation at dotss that do eot produce aonoorruunt lung
damaae, and they may t>rovide a good model for the atudy of iaseraetions betwsa radu-
tion and ehemical apenu in respiratory areinopenait.
h(oara.w .r a' (111 J Combined teeatmrnt of hamsters with a lowsffen dose
schedule of batao(a)pyr.u otus ferrie oaid. Sivrn intnttradtally, followed by a low dose .
of deMylnitrount,na r"t sysu+rutially. resulted in a aynerpsue tumor response.
Squamous alI areinomas of Ur trachoobronehial tract wm obsuv.d only in the group
receiving oombined trafsarnc; ad.nan'stratioo of single arcinorcns did not ausc simiLr
tumps.
Mo.ma+M n.l j I 22 ~: Curing the past deade eonsiderabk effon has been devoted
In the authors' laboraons te sM development of atre*inisintal modcb for ehe study of
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C'A;mieal Grcinonnois in Syrian Hamsters 17S
the p.thopenesis of lung ancer in eaperimentsl animals. The Syrian golden hamster has
been the st+ecia most extensively used. It proved markedly susceptible to various nspira-
tory carcinogens and conveniently refractory to ehronie pulmonary infeetions. Direet
administralion of polynuclear hydrocarbons into the respiratory tract was firu perfornktl
with colloidal Sclatin suspcnsions; most subsequent work nude ure of Rnely dispersed
ferric oxide in aaline as a arrier for crystalline carcinogen partiela. High incidenoes of
bronchoQcnie tarcinomas .cre obtained by the latter method, using benta()pyrate and
farrie oxide. The tumors n+ost frequently obwrved Were squamous ell ortinoeutv
Rapaated intratnclwl instillatioro ws most effaetia, although some tumors oadd be
induoed even by a single adminiuration. Direct dou-roporue eemJatioro were dernon-
prated by aryin5 tHe number of administrations, their frayuenoy, and the levels of taeb
dotie given for dilferent lenpths of time. The systerr.ic oarcinoScn dfethylNtrofamine wu
uued for dou-.esponse studies after tubcuursous adn+;nis..auons to adult or ntnrbmt+
hanuters. The tumor response was eonsiutently localized in the upper respiratory tt.a;
only a few tumors were tsen in the broechi and lungs. When such systemic esposwe.u
combined with Ne intntrscl>eal administration of bsruo(a)pyrene and ferrio osid or
a.en of ferric oside alone, a rtarked ttynerSistie tumor responsa was observed in the lo.a
rapiratory tract. The role of the time sequenee, spai6city, and dou of the fanon involved
In this synergistic action is prasently under study. Other topical and systemic rsp'tratory
nrqnoSeru have been invsstipted in danuw, mia, nd rats.
PoaT fl.l. (177): Acvte changes in the surface morphology of 6aretter traehoobroa
d+ul epithelium ware examined by sanninj ekctron microscopy following ietratnchatl
administrauon of ferrie oxide or bento(a)pyrene absorbed to ferric oaide. Multiple institla-
tioru of ferrie oxide brought about a Iost; of ciliated cells and broad arw of abnormal
enlarged nonciliated cells with roughened or wrinkled wrfaca. These were interpreted as
areas of epitAelial hyperplasia. Multiple intratrachal administratiau of bsnso(a)pTrena
and ferric oxide caused similar changes and. in addition, produced spuamous rnetaplasu
nd small foci of eurkedly abnormal protuberant alU. These /indinis an oertelatad with
previously re9oned observation obtained by trsnnnesion ehnron ntivoncopy. The
results suggest that scanning electron rnieTOseopy, is useful in studies ot the Antogenesis of
lung cancer.
lorr n al. (1)9J: In order to teu air poUuuan for their'oasible induetion of au+ron
in the respiratory tnct, animal e.prrimatta are noo4ed to invatiptt the rank of ontino-
Senicity of sinSle substances and their eombinationt. Our studies will contribute to clarify
Ue dou-raponse reiation and the retenrion of benm(a)pyran (OP) after intratrachnl
in*tion in Syrian liolJen hamsters and tubeutneow Injection in NMRI miott using di(t fareat
carrier liquids.
Three groups of hanssters wen injeet.d .;th 15 nK IP iarratrsu{soly divided in
IS single dow of NO vt in 0.017 ml. One group rea.+.ed iP solved in tnaprylin, the
second OP as a suspension in aaline with 2% TMean 60, and the third group raodveJ SP
like the s.cond ritA dded 130 µ5 atmaphrie duu per injapion, amountin5 to )t mt
dust. The ir dvn had been colleaed at lochum in fall 1963. Tumors in the respiratory
tract derelupsd in 2 animals of the firn poup, in 14 of the saeond and in Id of the third
group. In the last group the latent period was thonened. The twults after in)tetion of
tmospherie dust with OP ars not )et tufficwnt for estimation of the anceropcnicity of
airborne dust. The low tuma rate aus.d by the tlP solution in triapryhn may beeaplained
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136
with the rapid elimination or HP from the lung. After inarsuadual injation of 2.000 v6
BP distolvtd in triaprylin, only 13'/. - referred to the BP tmount detnmfned imme.
diately after injation - were deteeted in lung and traeha of ha+enters after 24 h, 0.1%
in rati, repeetively. Using saline as arrier the valua avt )2.3% in Aamsurs tad 6)Y%
in tsu.
Daw.r.rsponu relations of DP were investigated in mioe (strain NMRI) after a sinpk
twEcutaneow injeaion of 25. 30, 100 and 200 ps in 0.5 m1 triapry)ie and 100. 200, I00
ttnd t00 ui BP suspended in salim. TLe tumer rate nused by 25 yp BP in triapr>lin was
similar to that of t00 tai BP in wline and aaa found to be about 30!: aher I year. In tha
eayt there wre larp diQerencts too in the retention from t+ppliestion region dependcnt
on the tarriat liquid. Applying 0.3 ml triapryfin as arrier the auaatitr or BP in the
applie.tion resion was df, 27 and 6%. rapati.ely 7, 29 and !0 days aher .ubevtaneotn
iqjod'an. When saline was usM, valua of 111. 2 and 0.4% were found. BP elimination was
mou rapidly with Colrethyleneo,tide wEieh is an eaoe!!wt aolrset fac DaP and mi:a vNl
with body Ouidt. (AuMo»' aluract.)
Pruv er .f. (130): MacrophaFe count was studied in )Wnuters following a tintle
intratnetwl ieuuA4tioa of tritium labelled ('H)-bau(a)prra+e -('H).BP mi.ed with
orbon Wsck or asEeata. More atwophapd oould be found alter Me adminiuration of
('H)-BP + carbon black or aabeqaa, than afur tha administration of ('H})F alone, but
eM Mio.etivier 0« ~O~af ~at ~ di~ m ttta poup n.aud with ('H)-,P abns.
Tbe total ndio.etihty of the lurtt afur washing out of the snoephaBa was also studied.
It was the tamn is all tltnm groups durini the Mt week of t!e aptetiment. Later on it
prored to diminish mrns rapidly in the lirnt group of the aeiatak to Msicb ('H)-QP.lone
wu administered. (Autboet' abatraet.)
itt>donSat()uu and MoKa 1132): Syrian poiden hatmtaa ..n aested iotn
traeheaUy with 0.43 mg beate(a)pyrsne (BP) a+a wakly for lifa. !'ashoiopioJ chanyet
eavninS in tAe leonehi wen eaamined from the dtlh to tde 2Ut ..ak after beginning B P
treatment. Afl mmpiwlopeal prdiw vtrs perform.d fre.n uanithia sections hich
aUo.Ad (or eeaet erientation of tissues. The development ef bronehoyenie adenomau
from the sarllw tsup olslight eNl proliferation to diuortion of the ttaiement mnnbrane,
growth of epitAetisi toordt of tsl4 ieae the ltuu ti.uuo propv aed /IeaUy fortnation of tAe
tutnot are demotutated.
Arsr+a.SrnOu.ta and Maea (1331: Ep;+JkJi.l ak.ntione ooeurriei in tlse trseha
of Syrian golden lartrters treated onoe weekly for lifa .vith 0.6J nill BP .ere etumined
by mnns of deetron n+ioorcopy duriaj the Ont 20 wesks: TM ultnun><turttl leatures in
the ehanpt frorn normal epitAelium to hrperplastie and then tQuunota mwpluuc epi.
theliutp and Ma)ly, to papillonntu ue dnaibed and diannwd. It ia danoruvaud that
the keratinitinp precea. ef epitAd'wm undvdoind mwp4w afur BP treun.ent eorrs
aponde to tM patars dasiped for tae paauta) dwdotment of tiott karatie in the skin
of nanul rns.
Rts+eaSctOtta and MoN. (134): T1r ultrzunKtural alterations aavrrini in the
bronchial eptheliuT of Srrian golden haeuurs treat.d once ..ekly for life with 0.63 mp
iP were tnumierd during tJr Mt 20 woeks of treatment. It *as demonstrated that
spitMlial esl4 psearated ttte basement membrane thus llaally fonning tmaU bronchot;cnie
tumors (adesomata) oanpo..d of'eili6u4.oeeilfuad aedd few parl arlls. No squamous
metsplatia eaOrr.d.
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CAemieal Cueino6enesis in Syrian Manuters 1"
RtZ.ntScwOusa er.l (133J (sa also p. 145): The e!lects of two types of tesardt
cipretta, which diRered in their total smoke delivery and cnndensate, on the bronchial
epithelium of Syrun hamsters nere e:amined elecuonmicroscopically. The animab were
eapoisd ona a day for S days each week for I year 10 the total smoke of the cirarettss. T.o
groups and a ironuol,Sroup were killed I day after the last ezposurc. and one group
12 months after the last sxpo:ure. The bronchial epithelia of all smokeeaposed anirnals
were bYpvplauic, .nd their ultnstructun showed inratieutions, tilt of nut:ka asu, an
Inanaie in the suenbv and sine er lysaeaew and awltiwaicalatad bodies, and inayased
suatbees of talar'ed intnmitoeAondri.l Fsnnls. Spuamout ntetaptasif, rarsly found,.w
preent at Me sup of lilamentous bundle formation. The induesd alterations .w isa
dependem of the type of cigarette wed. One year aher sr.-kinS irs Urmiraud, the
alterationt had neither rersneJ nor adraneed, as oamparsd w.err. nxurrinB I day after
tbe laet smoke esposuR
Rozw e af. (/S6J: A wnisynihetie diea for hanWers was developed to awdy the
df.d ol riumin A on ehemieal areinopenesie. The d+a an be adapud to uudy other
nutrientl as well. When retinyl palmitats b used as the s.oura of vitamin A, the stmityn~
tbetie diet supports nonnal Browth and development. When essinoie aud is ueed, aowth,
spen+suopenais, and teetlcular size are deaeased. Hos+er, vitamin Adeflcient hamsurs
tespoeded to rstinoic tuid trntment with weijht pin and inerased appesite. Within
2-4 weeks atur withdnwal of retinoic acid, the hamsters again showed sijns of dcRciencY.
Swnvrn (1 sIJ: Three maio types of twnor rseponw have been obtained ia eaanseef
foDo.v+S diRaent kinds of trtatnxat: (1) Squamous osll earcfnomss of the bronchi and
of the laryna companble with tlase most frequently uen at theae two sites in man art
indund by intnrtrtcheal insulLtion of polynut9nr bydronrbone with appropriata ar.
nas. This treatment also iaduas squamous osll eudeortus, papiUonus, and polypt ia
the trschea, enaplastx earcinomu and aderaoatoewmae in tbe *onehi and eome broet-
eluoLv,al.eolar tumort, nwstly adenanatous. (2) Multiple basipt papillary tumors of the
trscAes and laryn: ue induoed4 is a biph irteidsnot, by the systemic tart:inopst diethyl-
auvomine .rh+ch also induoa a vt+rie+y of tnmtors in the nasal a.ities. (3) Peripheral
pulmonarry tweon and other proliferati.e laiontr showing sevaal different morphological
sypa, tan be obtained by ur.atmmt with mattaiab tltat ars retained or meubalis,d in the
broetebiolo-al.eolar region, such as the aboK-mentiootad syuesnie nrenoten diethyl
saitrosamine, p.nicvlarly when given at high does or whes follo.+d by iatratrncbnl
adminiuraion of particulate tnuerial. Otlw apata shown to ieduoe pseiphenl tumors
ieclude ndiowivs materials or cobalt eiside piven intruraebeally. An apprwch to the
study of toorpboloBiesl biod+esnieal oorrebtions is the pathoppresie of bamsnt nspirr
toryy tumon u discussed.
Srvrom .r.1.1160J: Syrian golden eastrsas+ or b»a sota seaei.ed 10 intrasracheal
inuiltatioas acs of 3 mS benzo(a)pyrens (Bp) and 3.n bem.tie suepeaded is 01 ml
saline. One group rsoci.Kd oo funher trratmem and derebped 13 Mryuewut tumors and
13 nsa of sauamoau rnctoplasia in 3) aaia+ak at risk. The faorb patp. I..eh after the
end ot Jre Bi'tratarat, uarwd to rrocne t.ia.aeklr stonuch tnbe (eedfnp of v(tannin A
palnutate (3 mj or 3,000 IU in 0.1 ml eoro oil) continued for life. In this group of 46 ani-
snals at risk only I dereloped s mitTOrcopic squamous tumor in a bronchus snd 1 de.el
oped a patch of squamous nuuplasu is the Jnclea. The incidenos of forestomeeh pspil
beav was also r.dueed msrkedly by vitamin A treatment. The authors supqest that
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vitamin A has a systemic inhibitory effect on the induetion of syuamous chanm (,Ma.
plasia as well as benign and malipunt aqwmous tuntors) in the columnar mucous epi.
thelium of the rapiratory tract.
S.rnesrn rr d. (IR11: (knzo(a)I+yrene (oP), pnaand as a'"pension of fine erystole line p/tnielca
attached to Nrticle3 of ferrie otkk in 0.9% NaCI aolution, was administered
by intratrachcal instillation to Syrian golden hannten.
A sinak administration of I1.3 rn5 DP with It3 Tk fearie oxide in 0.5 ml 0.9l;
NaC1 solution induced Ave bronchegenie areinonus and Gve histologically benign respira
tory tumon in a total of 61 hamsters. A single adminisration'of J mg BP .ith 43 mg
ferric o%idc in 03 nil 0.9!; Mi(1 ttolutie+n induced one Peripheral adenoan:inoma and
six histologially benign respiratory tumors in a total of 119 hanuurs.
Ret+rated instillations, each of 9 tn5 SP with 3 mg fenie oaiJe in 0.20 ml 0.9ti NsQ
aolution, wene adminatered S. 10. or 13 tima; two atperimatul =routx were used at each
dose level. Respiratory tract tumon, mostly broncP.otenic arcinomas, were induced in
all Sroups, and a positivs doseraPOnse relationship was demortitr.ted.
Sntatuta er al. (161J: When given intrausehcal injecsions of a snspension of
bsnzo(a)pyrenefertie oude. rou and hamsters show.d strikie5 spxies diRerences in the
response of their respiratory tracts to the arcinot;en. Hanuters produced squamous
nmuplasia of the trschea and large brtsAd+i; in oornrast, aauamote edl nodules of bron.
e9tiolo.l.eolar origin derdopsd in rats within a few .wekt after oueinoprn application.
The difsrent aita of the early prolifastive aod ancuptsstie raponsa corrsJaud in their
{ootion with tM sitew of later tumor derelopmau. There were ta osvioua diRerenees
letueess the two sp.ao in «sanion of fP Ia the lunas or tneAeu. A apeces diRervus
ru observed, horera. in ths loaliratioa of the !P in the trachest tissun using ullra.
viokt nuoretoenas atioroeeetry. Caroirrop n wat foano to be prrsent in the epithelium of
hamsters but not in ths epitheliuat of rata, tupeatin5 a spaeia diRersna in pertctration
of carcinogen fran the lunxa+ into the trsdwl tiows.
SCNaruea er.f. (161, 1651: Thr e:foliative cytology of the lung was studied during
the induetion and early developnent of napratory eraa tumors. Syrian golden hamsters
rsaived multiple intratrsclxal injeetiotu of bauWa)pyreneFe,Or for II Weeks at a
cumulative dou of 63 mj OP. Shonly, aftar the stan of the experiment a terere, probably
toxic, cytolopsl raporoe to the ardno{ee application vas obssr..d; thit response
rapidly diminished durina funher irljtetiom and disaPpeared after atsaoon of aranopen
administration.
The avera6e time Imerval from start of arcinoden application to death was )7.S
.ecks. During this time speciment tevealed a progocasion from mild atypia of spuamous
meuplauic allr, to moderate atypia, to marked atypia, to sh.nSes indicative of cancer.
T1w arainopcn.+nduead orogreuive cytolopial chanpp tho+ed striking morphotopial
aimilaritia to tytokos,nl cfunpes described in ciprettt smokers prior to the development
of lung taneer. !y tht 2lth .eek of the aperinwtt, apecimau of all eardnopenveatad
animals 6.d cells wqatew or conclusive of aneet. In animals that died ahrr the JSih
waek, the diagnosis of anm had been node at an avarage tin+e of I9.eeks before death.
while in anitruls that died bn.een the Ilth and )Sth week of the experiment tM dup+osn
had tsot bien made etrla than 9.eeks before death.
Sensitivity and stecikuy of the cytological anetlwd for diagnosing cancer were very
llah, since no faiss nesati.e du{noss.en made in tumorEannS animals nor wcre false
C ~' F~ H N 0 42 1~"~~
re
l
Is
a 1
(Temical Carcinopencais in Syrian Hamslus 139
I
paitive diage+aee nude in control animals that received Fc,O, alone or in arcinocen-
trated animals that did not develop tumors. Cytolotical typing or nulign.nt tumors vr,ns
cfficientfor histotopically %elt-0ifrerentiated tumor types.
ScHatiacta e/ el. (I661: A method for the induction ofaranomss in r tircumsefibed
rLllion of the hamster lrathe3 is reported. By means of a special atAtle-, a Wl.,tion o/
N-nitroso-V-mnhylurea was applied twice a.esk to about a(-mm kngth of the tr.cAea
10-16 mm distal from the vocal cords. Slight aturation of this catheter allo .ed samplinB
of cytolotie specimens directly from the surface of the arc+nopesalpaed epithelium.
This proccdurs permitted the simple and aaurate eanlatior. of wouenilal listolopo and
trologie changes oMerved during tumor development in the hamsters. Nooinvesivt dys.
plastic and meuplastic lesions were seen in animals killed after f and 10 .a:ks of ar-
etlno6en tappliation. These epithelial changes could be radily oorrstal.d vtls abnoreul
afoliated alls abundantly present in cytolopic specimens from uMe animals. Euposurr
to arc.nopen fct I S weeks induced a YOO% tumor incidence aclwrv.I- it the application
site. More than 73'/% of the malignancies appeared within 15-20 weeks aAer the start of
arcinopen administration. Most tumon were epidermoid arcinomas but some anapiastie
Iargeesll arcinomas were also observed. CytolotK specimens of tuma-bearinj animals
had many alls conctusive of malipnancy. The ne.r aperimer.tsl sysurr. knds itself lo
study of the eQ.ct o( topically applied antiarcinopenie or eoaranot,rruc agents on od-
fcrem arcinopn-induad epithelial lesions whose regression or kopeasion can be tol-
lowed dia6nostioey by e+Joliatis cytology.
Stu.atuwit et d. (167): Dose-response relationships for adnvniuntion of wr
pensions of diRerent dosages of ferric oside and a constant quantity of BP given intro
tncheelly to Syrian golden hamsten wen enmined in this ewxlsl sritsm for respiratory
arcinolenais. Each group recxi.ed 10 ientilDtions at 2-.eek intervab. The amounts of
fcme oaide were 3, 6, and 9 m6 per dou, all with 2 mB of BT. As prevwtsr, nolad in this
animal model, squamou all areinoeua .ere the petsdominaM nwrpAolopic type of
induced tumors. and the brptchi were the moot hepsundy aRect.d. Earsnuully identieal
raulu were observed for the lhne eaperimentaJ poupt. Dow of faric oude beyend a
1:1 ratio with BP did na enhance tumor yield. Thess tasulu demonsuu.d that beyond
a certain aiual ratio of BP to terrie oside, the proportion and OlauWy of ferrie oside
aImini:tered wsre unrtlaled to the incidence of indueed :umorL
Stuw.w.a and SMUSae (16t1: Two Sroupe of aale Syti. poldes A.ntitan
reoeived. repactively IS and 30 weekly imrnrachnl 4utilhuone or 7H-DIlC suspended
wiih an eQuat amount of hematite in saline. Both jrojp had high i.ad.ne. of tumon in
the respiruwry tract. In the group tAat teaiv.d the hiSW doM (4S as total). 30 of
33 animals (16ti) had respirstory trsa tutsors: !0% or the tvn.ers .wre tQu.movs cell
arcinomas, with the Arst tumor appearing ita the broneMs as ear9y aa the Ilth w.ck. The
lumiters lrnted with the lower dou (!f mB total) had simlar ino~0a+ae of respiratory
tract tumors (t9/.). In this group, 64% of the animals bos & tosal of .I lpuamovs aU
esrooomas, .ntA the Arst tuaroe appearing in the traelw sit the )Ota ...k. Mou tumors
in both groups aroee frmr the epithelium of the bronchi and umcfw: a f.w aras in the
Iaryns. The pnxnt result demonsvata the high polent arcinooeme ocuvNy of 7H-DBC
in the respintory system.
Swm/ n.l. (17a, 17S): Male Strian hamsters fed a commercial d+a .e.e 6wea a
seria o(12 intratrachcal instillatioro of 3 mp bento(a)Pyrene adhennt to 3 o+y FI,O, in
L]
Cti i'"w. HN S..A `°11' 2rtf .i. 3
:I
Ho.auacu 140
01 ml 0.15% NaCI at weekly intervals. After the last instiltstion, the hamster: were ran
domly aaipned to recei.*eithcr 100. 1,60D, or 2.700 (later nduoed to ),4001 vb rnrnyl
aaa- ie per s,oek in divided intrapstrie doses. Hamsters ie the 2a00*{ retinyl aatate
group had a ei6niReandy hiSher inciJeM of respiruory tnet tumors than thou in the
group given 100 yp retinyl aesute pet wsk. L'rver vitamin A tJore inertared dranutically
In the groups piven 1,600 and 2.400 µ= retinyl aoeute and eroreesponded to the admiais-
tntion of rctinyl acetate p.o. Serum vitamin A values were tat oonsinently rdated to
retinyl aatate sdministmion or to hep.tie stores o( vitamie A.
SnNaxeu (1771: Intratraeheal administrations of pentopyesne in ferrie oside into
Syrian polden hamuen were uud so study tbe development of lung tumors, the penicipa
tion of dirterent tiuues of the espirstory erut In the neoplastiee propasion, the sipniR
ana of prencoplastie alterstions and the mor9ho)opal ebaraeurietia of the reapirstory
tumors produor.d. The progression of the e.oplastie stats was divided into thne stages.
Fint was a reactive phase oharseteritad by ponspsciik alterations: e>;lioeytophoria. slit
formation and espulsion, basal eell hyperpW" mucous meaplasia, squamous metaplasu
and squamous as well as edenomatous h)-perptasia. In the presutipnant phau an adenoma,
spuamow pspi)lomas. a well as srruamous dysplasir and eareinoma in situ like cLanea,
aere seen. The malignant phase showed tumorn apporendy oripinatinp from a common
p.cvrsor di/krentiatint tp eypiasi udeno u+d sauamous oslt audnoma, a iarte all
oardnomadike tumor oatvniey very late duriop the eourw of the therapy.
It was ooec)uded that the hamster oBsrs a good nadd for morphologic audies ot
nepiratory neoptasnn similat ia dev.lopm.at nad dtaraetsristia to thae of the human.
SytN.:at n.l. (17l1: The ardoopenie eRect of dimethylnitrosamine (DMN)
itye^ted subeutaneously iu Syriaa golden fDamtars as wdl s the synerysdc sRsct of
iatrstrsdwl iasullations of ferric eside .as atudisd. DM1i Vpne induced avernous
henunpiomas. hemanpioendottrcliotoas, ~iarareoauu, ae wdl ae enm
hepetoma of the li.er and ons pspilbma at the foeatoeaach, but eo tumon of Me rapin
tory system. When ferric o.lds .nas given in addition to DMN, liwe tuman of vascular
and biliary origin were saee, is addition to tumon of the eusal aviey, aewoepuheli,l
tumoes and one adenoau. It was oonduded that subauaneously injected DMN u a
powerful hepatic artieoSen for the SyrittA golden hunuer. producing liver tumors of
vaseu)ar, bile duce as weU as liver oe11 origin. T1r lack of tumorijeeic eRoct in the
respiratory systern vres considered to be due to tbe laek of tnetaboliun of DMN te ths
1ung.
Sto+a.:cn and Ssu..nuw.a (17f1: Repsaud tatrntrachcal insu7lttione of 7,12
dimethyibau{aknthrsune in the respi»torY tna ol Syrtian golden hamuers induced
popillomas, arcinoma in situ and sauamnus eell arcinomat of the taryns and tracha.
The neoplasae progression was characurisd by pronounced and e:unuve squamovs
etetap4sia showing evidence of Syperorthokeretocb and hyperpartkersto+is. .uho.n
a.eeedary ehanja, inAamnuuon and bbroaie is the lung. 7Ds total number of tuRwn
wea, 20 and 17, respnCtivdy, the short latent period (20 or 21 weeks) and the low do.a.
0.15 and 1.2 nsp in totaL rapeuively, edow tAu DMlA ie atso a pount earanopm m
the raspirstory eystesn
Snxeitu and Sauttnua (1901: Onr ny or DDf' for 12 a+.elu er 0.5 ms for
17 .eeks, instilled inuutrschatly onee s.rssk induosd tumon in the respiratory system
ia 67Si (0.! mp) or 7!A (1 mg) of the animalswith a latent period of i w.eki. Histolosx:*1ly,
~`-ipR t1~~ 0~~:~'~` ~ 4
r
I
Cheatieal Gntinotenesis in Syrian Hamsters 111
tIK tumors *ae mostly aquanwut aA nreinomu, the most oommoa kxation was the
bronchi, followed by the trachea. The siSnillana of theae Bndinp for the ausatioa of
IunS anar io man u discvsud.
Snaa and FuoM 11 t.J: Lung tumors induad in Syrian golden hamstera by multi-
ple iatratracl+cal instillatioeu of diethylnitrosamine (DENA) wers studied with rpd-titio
and el.etron miaoseopie techniques. Two dittinctivs typa at epitlxlisl alls oould be
idsatiried, (a) tmall, qtoloaially fairly undiRsrsatiated oe14 and (p) 1arser w.ll-diQsr-
setiated oeltt elosely resembling rtornuW type I( Pneunacytet No squamous epitbdium
.a rouad in the tumon.
YJII. Inho/otion
Inhalation studies continue to be done in the Syrian hamster because of
its relative resisuaa to nicotine (12) (an advantage for smoke exposure) and
~ its nearly absolute freedom from spontaneous lung cancer and areinoma
of the upper respiratory tract (116) and from rapiratory infections. In one
such study, concentrations of 0.5 ppm of dimethyl sulfate,'6 h every 2.reeks
for )S months, caused signibant incidences of respiratory cancers in mice,
rats and hamsters (162).
A series of studies by DRxw tt o1. (32J, Kuse>«tHOt a o1. (97] and Lasux
er o!. (100) demonstrated the toxicity and carcinogenicity of a-halo-ethers
(chloromethyl methyl ether and bis(cbloromethyl)e tberj. The arcinotenie
effect in this case was more marked in the lung of rats than in the respiratory
tract of hamsters.
Otber landmark iohalation studies aro those of Dowrxxwttt (30) and
DorrtENwtt.l et n!. (311, who reported at the Conference on Inhalation
Carcinogenesis (Oak Ridge, Tenn., October 1969), and later at an NIH eon
ferenee, results of the exposure of randombred Syrian hamsters in a smoking
machine of their own design, which produced about 10.6% of preinvasive
arcinoma of the latynx and a bijber incidence of inetaplastic and byper-
plutic chanja of the tracheal and larynjeal respiratory epithelium. With
more sophisticated inztrumentatioa deliverinj known qwntities of fresh
smoke, and with inbred Syrian hamsters known to be susctptible to poly
ryclic bydrocarbon arcinogenesis, we have repeated pan of DoNT1l+wut's
inhalation studies with similar or even more striking resulu, since nearly
20!; of the hamsters inhaling Rl Kentuckyreferenaeigaretteslfkd squamous
cell carcinoma of the larynx (13). In addition to the tracheobryngea) changes,
two malignant tumors of the nasopbarynx (one of them with lung metastases)
have been observed.
11
~~ ~~ ~~~~~~ ~
~
i
I h
Howauacu
Ad k
142
Hamsters are now being used in studies of cigarette smoke inhalation
to test various types of cigarettes by comparing their eRect on ultrastructure
of bronchi (13S], and to explore the cnrcirlogenic or.coarcinogenic action
of cirarette smokt. (coarcinopen for BP), according to KoaAYAsHt er oi'. 1931,
or smoS and ferrit. oxide partides (12S). There ars few papers reporting on
hamsters during inhalation of various substances. One such study is that
of PAt.rtca er ol. (129J, reporting a marked reduction of BP hydroxytase in
the lung during inhalation of ozone.
Deawrtta and Harwacta (121: The availability of over 20 inbred strains of Syrian
golden hamsters nude it possible to docyment the remarkable lack of susccpuhilitr of
this species to nicotine poisoning and to demonstrate the atnin.dependcnce of thia
phenomenoa Nicotine was administtred in two ways: i.p. as the tar!rate, fotto%eJ b>
obeenation of the mortality within 30 tnie; and by exposure of the animals to 1:5.2
diluted, Mok, fresh smoke from Kentucky refersnos cipretta and recording or the
survival lime. Smole exposure .as aehieved in a tValtonMorrissey re+ersrsrtalinp
ttuchino which deliven sumessive I-min eycles, each consisting or a 17see pr,od of
smoke foUowed by a 13-soc period of fresh air. The LD of i.p. nieotine utvate, as deur
enined in aroups of S aninuls, ranpad from 125 to 320 ma/ka body weight in 6ve inbred
hamster strains; the lJ.16 lias ahib;ud the bitihest value. It .ru alSnilkantly towa in
rats (ti mz/ka) and emuidetably tos in S+rias tnica (13 trt{Jka). The toltvtiacs to whole
eiWetu smoke, e:prased as tnnn survival times in groups of 12 animals, was apin
bialKst in the 13.161ine o! harntters (244 etin); it ranpd from 16 to 178 mie in three other
hartwer strains, but these values did not paralkl tba oorraportdinp LD vatuea of l.p.
nieotie. iann!a. The totvanos of whole snwka vas esmarkably smaller, in ratt (20 tnin).
It is apparent from these data that Inbred harnstr, sstrains In Ssrwal, and ttr 1f.16 line
in partialvs ktnd tlKmselves twubly.dl to srnoks inhalation studies.
Duwrtn,a a.f. 1131: Male hanmas, 102 from each of two inbred hamster lines,
were exposed to cigarette smoke twioe a day,1 days/wek for up to 100 weeks, in a modo-
f4ed Walton reverse-smokina machine. Sisty sham-smoked and 60 npeheld controls
were taed for each strain. Smoke exposure for up to 100 weeks had no afect on morulity
in either urain, but reduced boJy siaht. Carboayheewalobin levels incsased markedly
immediauly after each smoke eapowre but returned to baseline levels in leu than 24 E.
Serum tri{lyoeride levels and virus proflb of smoke-exposed animals wa+e unclunped.
Chronic smoke exposure increased relative weight of the lunp and bean in both straiet,
but to different detroes. Over 90% of the smokesxpotad animals of both strains shoWeJ
hyperplastie or neoqtastie t:Asnpa in the laryna. However, microinvasive anar was
nearly 3 times more frequent in one strain than in the othv. In the inbred line rnore
susoeptible to lary"gsal hyperplasia, 2 animals developed nasopharynpal tumors, one of
which was eutipunt. Smoke exposure induoed rus benign sQuarnow papillomas in tAe
air passaps of both unins. The arain lea susceptible to tarynseal hypcrplasia eshibited
tnore pulmonary adenortutow, but its incidenice .vu not signifScantly affected by smoke
eapawrs. Oumpina of pulmonary nuerrophapa was proof that smoke had reached tAe
Wnp; one suain.ns more susteptibk to this phenomenon than the other. In neiUxr strain
did smoke exposure aRect the incidena of tumors aritina outside the respiratory tract or
the degenerative chanaa tdtaracuristie of aaina hamuers.
C~`R ~°'I~`~ ~~~~"~"~ ~
. a
Chemical Grcinogenesis in Syrian Haeuters 143
Do%-mxwiu. (301: E.perimenta were performed on hanuters, nies, and rats in an
eRort Io find a practicable inhalation model for IonS.term eaposure to tobacco smoke.
TheSe elperimentf were desirned to r1:Vaal all reactionl of the animals during patlive
smoLe eaposure so that the eRecn of passive smoking on animals could be comt+ared with
the eRecu of active smoking on man. The toaieity of several smoke componcntr, fuch u
CO and nicoune, and the compatibility of diRetsnt taposure pcles or dosages wsre
investigated; influeneet on rispirotory frequency, eounu of eryt)uocyta and lcukoette;
trdimentation rate, body vei;ht, and food intake during smoke eapoaure .tn also
measur.d. Monover, we baae tried esperimentally to elari(y the si6ni8onee of the stay
period of ardnogenic substanas in the lun` as well as the meubolum of carcinopenie
subr,tanata. Hiatolo=ial c)+an{ss in the rapiratory trset following longterm aposurs to
high smoke dosa are reported. By rtwsurinS auim:lsud "Clsbeled smoke particles, we
have uied to eaplain the genesis of t)t alterations that we found.
Dorrnxwtt.t. er.i'. (31J: Resulu of chronie inNlatioe eaperimenu on Syrian 6olden
Aamsters vers roported. Of 4.440 hamsten, 3.610 were used for their enttre lifespanro; the
tertuanin6/30 was expoud for no lon6cr than 32.eekt. Some aninuls received additional
trastment with nrunopene. Survival umes and body.and orran wsight development ws»
eorrelated with treatment or etorpholosic chan=es. 1athohistolo6ic invabpuoni, and
bochemiat analyses of blood were performed. Expain>nttal rewlts dcoroeuvsted a dose-
raponse relationship. Elfect: of smoke from various types of cigarettes and cRau of
combined smoke and arcino{en treatment wen evaluated. The results were u follo.rs:
(1) Clunges induced by smoke eapocurc: Striking ddTcrenas were found baween e:peri-
menul Sroupc. A/teration: were most pronounced in the laryna and depended on duration
of tratment and dosa6e; survival times were reduced, and loss of body weight was dou
dependent; the number of erythrocytp inerrased and hemoglobin rose. (2) CAznta en-
hsnced by smoke c.xposure: Incidence of'tmoke celL' wu peater; increase ie'adenonu-
toid Icsioni was slightly sipnd,ant. (3) ERects of tratment with DM BA: TAe number of
turtars increased in the oral avity, phiryna, esophaEus, atomacA, tradte& liw. and
ovary; the oacwreria of ovarian tyse also in, essed. (4) f.Recu of eitroaanune wtment:
Papillomas in the trachea and lower region of the laryns differed from those in animals
eapoud to smoke. (3) Changes not connected with Ireatment: Findinp included stomach
ulcers, pwitit, pulmonary emphysenu, inflamemtion of the respiratory uaet, peneralired
amtloidosu+ tesucvlar atrophy, vascular and heut disates, ewscvlar atrophy, fornuuon
of thrombotia in hesrt and lungs, eardiomyopathy, inflammatory chanees rn the soh
tisaue and intestinal orpna, bile duct cysts, bile duct proliferation; also tumon of the
na>JI avi(y, skin, connettive and supporting ti.wa, hcnutotwiceic systm ond asiruul
jlrnJs, and biochemical nnJ lk,tutulopie elunps (apan from ehan`ti, in er7ihruaia
and hrmo`lobin).
Catw n a(. (321: A range of acvte studies were performed with cMwone.lryt ms,hyl
ether (CMME) and bis(chloromethyl)cther (6CME1, ineludina !d-da7 LCv.a (oonoenua
tion kthal to 30/% of the animals), following eirtdle 7.hour iahalation «paures. The
LC,o for CMME were SS ppm for rats and 6S ppm for hamsters. The LC.r for BCME
were 7 pom for both spaxs. A1l aninuk ahowed eharaeterettie ehanges of acvu trrnauon
of the respiratory :ract numtested by congesuon, edema, and hemorrhage.
Severe u+oncn i; of life span was sesa'ie 30r)ay eapowres of rats to CMME and
in all r,tudies.ith OCN1E. lncsicnees of mucoul ehanset,, including at) pLa) weie esnerslly
CTR r,,. ,,,,~ .~
"~'~ ~~ ~~.,r ~.
Ho.nuaou
lat
inerased in a dou-reiated eianner in ooth species. The arc:nopcnicity of BCME in thee
range-finding experiments .as demonstrated by a ikio cancer in a rat after t)uoe eaposuret
and a nasal tumor in a hamster aher one apaure to I ppm BCME
Ko.ev.sut er d. (9)(: Four poups (23 auks ach) of Syrian golden hamsten were
treated as follows: Group I aas esposed to ciiarnu unoke after intratrachcal instillation
of 2 mp 7,12dimethylten:(alanthrarna (DMBA): Ipmp 11 vis exposed to cigarette
amoke without the initial dose of DMYA; group 111 r.aa.ed DMBA alone; and group IV
(controls) recdvrd the vehicle alone. Hyperplastic and neoptastic lesions. mainly kuko-
plakic chanpes, developed in the upper respiratxy tnc% espociaily in the larynx of
poup I hamsters in a sipnif.antly higher ineidena and earlier than in the group If ani-
mats- Other lesions in poup I hamtters included spuamous call metaptuia of the nasal
avity, sauamow all Npillonu of the oral cavity, and pharynpai keratotic papiiloma.
The rauiu demonstrated tun+orpromotini and(or ooareinogatie activity of cigarette
amoke to the haeuters' upper rapvratory tracts.
Kvse-4wut er sl. (97(: Rnu and hamsters were exposed to 0.1 ppm bis(chioro-
meth)l)ether (BCME) 6 h.er day. 3 days per.tek throughout their lifetime. Additional
groups of rats were pven :0, 20, 40, 60, $0, and 100 apaurs to 0.1 ppm BCME and
t)ten held until JeatA.
Forty anan oripnatnp in the respiratory tract were found in the 200 rau in-
rolr.d in theet qudpea. Th.e included 14 aeoea of the lung and 26 au+oers of the nasal
cavity. They oeamd in dor+e4t.d fasbion. A dn6te undiifaentiatad arcinoma of the
htnt was rtea+ in a bansMr.
Lscrw n.f. ( I00( :Rau and hatnten .ere tatposed to 1 pprn of chloronKthyt methyl
ether 611 per day. 5 days per .+ek, tlrouphout their lifetime. Mortality and.wsijht pin
of the uposcE ass.rb pcntWed that d tha cootrol animals. Malignant tumors d the
respiratory Eraa were f wnd in 2 nta. 7hse were a t9uamout call arc+noma of the lung
with biood veaul invaioa and an easheioeavroepthdionu originating in the olfactory
epithelium and invading the forebrain. One bamster was found to have an adcnocare9noma
of the lung and another a sawmous papilloma d the trachea. A single exposed rat bad
a piwitary tumor d primitive oell type that may slI have been coineidsntai.
Nc-aMUr er d. (12S(: The artinopt:nie and oasrtinopenie aaivity of synthetic
amop, farrie oside (Fe,OJ dust, and a misWrs d the two air tontaminattu was determined
In a lonp-term inhalation study with Syrian haewen. Inhaled Fe,O, particles deAniuly
enhanced liethyleitroaantine tumorilenieity is the peripheral lung. Synthetic smog did
not. When tasud at a ear+an,ration of 40 ppm methane apuivaknu or 40 mE!m', rapec-
tiveJy, neither atr pollutant by itself appeared carcinogenic. Fe,O, caused pulmonary
Abrosiu and trynthets aew6 caused alveolar braocltioilration in many of the exposed
anieeals.
t+twust er.(. (I291. Eapo+ure of Syrian (,wlden hamsten to intsassin6 concattratioas
dosar dareass banqrtresne hydroaylaae activity in the lunp as much a 70/...hik the
bn>spyra+e hydroay4r aeuney in the liver remains unchanged. The defne of inhibition
it the same for both wilaalty induad high enzyme lereb and normal, relatively low
eazyme levels. Lun(i wsedu ecmpariso"a ars teed to show that dilution of the ensymee
t.eondary to.dem. form.tion, plays only a small part in the reductions in enzyme ae+ivity.
Oyene may aet ar a eeanonopen with inhaled benzfa)t>n~ by delaying the eneynuue
tnndormatwn of the lydroarbon.
L
1
CTR HN 042 -0 1 E3
Chemical Grcinosenab in Syrian Hannters 143
totm tr.i. (111,16ll1: Spontaneaut retpintory uut aaoplaanr ia Syrian banstM
oaurred in almat equal frequencies in two eo/onies: 3% in the Eppky Colony (EC) and
3.6i% in the Hannover Colony (HC). Neoplasnn +ren in the satsl avity, traehn, and
lunq, and most wen bcniant however, 2 adenoeareinomu of the nsaal cavity (EC) and
I adenoarcinoma or the laryna (HC) were fouind. The incndenot of diseuive aract tumors
showed a more marked diRerena than that of the resp'vatory tract: 7% in the EC and
13 % in the HC. Dieatirs trsct tumors accounted (or (S and 41 % olall tumoea in the
>rC and HC, retpectivsly. All EC dipativa+ tract naopiasmt were ttmi=n and oaeute~ad
statly in males; 19 ({3S4)wsrt fotestontacA plpillotnas aad the rainanina 6(17Y.).rere
liver Itantane;oeadotheliomu (2) and p.ncrntie dua adaoomat (2). Ia the HC, almoat
JO'A of the dipectire traa neoplamr were uWiSnaat aad most frpuaat in farola. ?1we
tumors included 19 (62h) intestinal aderoaremomaf,lf (e0ti) G..r a.oplama (1Kman.
Eioendotlxlionut, eholanpiomaa, eholansioareine:nas). !(13lG) fonuomaelt papillomas,
and 2(6%:) gallbladder polypq. The morpboinp of theu neoptatna was reported.
RatmtSatUt.iu et.t. (133): Saa pqa 137.
Stnudoa aad D..n+sCM (16:1: Golden bartwttrs, Wiaar rau and NMR tnioa of
both taw were esaosed to 0.3 ppea at dimahyl aulfate (DMS) twios weekly fa 6! and
in anot)w wrin to 2.0 ppm DMS every 2 weeks for 6 h, altoanher for 13 oamhs. The
tota/ obter.atio>+ period ws two and one haff yan. DMS wu pa+ersted try tlrrmatatie
evapmtion of a ooetstaat Row of liquid fran a 4rae wrfaa ia asadalika steps. The
ana)ytia) control or oonomtta/iom was arried out by a tapreial gas e9troeaatopafhie
tmpod. Each 6-hour euposure to a concentration of 1 ppm aused e+arksd weight ba.
In peneral, the weights of all tratad species laned beltind those of the oontrols. !a euoa
the survival time was shortened by 21 `.i, in nu by 60%. A!I aper+ntentsl animals
e:bipit.d atarked mivoscopie and mseroetopio iMaarnatory changes in the lunp which
beama the causes of death. Lunis and trflehtat .ora thoroughly a:aasined by ate9.i»
serial seaioning. On the averap, 10 aaimaL were thue asaminad is each tpaia and acs.
The following tumo+s were thts foued: i aanl arcieoteaa, 3 luras ardnoatar, I tboraoe
arooma and 2 det sneratini pultawwar7 sidenoinies. %Wan tulmoaaoy adamaas omtrred
wuA epual t~queney in trea ad and is control animale (! and 7). The aroino~enie aetiruy
of DMS, whicfi Aid baat awmed based on paratttrsl aperiaKatb iu atereby oooArmed
for the inhalation touts. The maaintfl pertnissibla earoentruion. hitherto aooepted as
I ppm, i. mucA too 6i{A. (lAitor'a ttanflatitati)
An area of the rapintory traet susceptible to arcinoScnesis is the
nasol i-pirhelium. While VAN Hooatt:u et el. ((91j did not report any spon-
taneous nass( passape tumors from eithet theit own oo{ony or from the
literature, Pouzt ef oL (14=J found two mali=nant tumors in asaks and one
benign nasal tumot in a female of their Eppky Iauitate oolony. There was
only one benitn nasal polyp in a fenuk of the Hamburl colony. In our own
studies (13), two maliSnant aasal tntnors were induced by aprette smoke.
Dolrrtrlwlu. [30j, ia his inhalation studies, could not rdate the inhalation
of smoke to the few aasal polyps which he observed. Graaruu7T and
RuttSrr,CHAnn [S01 reported that t.e.;injections of DEN or DMN produced
olractory epithelial necrosis, which was doserelated.
'~ "~° #~ ~~~~ 04~ ~` ~. ~~
I
Ho-mwRca 146
Gr<caiPurr and RuMS1+c11am (30): Diathylnitrwaminr (DEN) and dimcthylnitlo-
aamine (DMN) adminiuend pupnerally into the Syrirn golden buroter, produad
olfaaory epitheliat nocrosis in concentrations :eater than 10 e+{/k{ within dt It. The
aeverity of the necrosis .as dosarsLtsd. Bob compounds were equally alfccsive in produc.
ina olfaaory epithdial ntcroait when compared an the (fas's ot trulGiram of compound
administend per kilogram of body "phl. Ho.sw. from the t.D.. krsls. DEN sas a
far mora'efeetivs' naaal toai4 Altarriiont in the olfatdery «pittKlium produeed by DMN
wera alays paralleled by merwitina central lobular dhatyir is the liver. DENdosed
animals had pronounced olfactory epthslial alteratian with 4ttN or no hepatic changes.
BoM compounds eahibited remarkable tkiaeti» toxicity for the olfactory epiihoiiun4
aapacially the sensory eells. The cytopaUrologk atserstiom appeared idmtial, nkardlat
of the compound used. Respiratory type epithelium of the nasal arity and Jacobson's
apa were rslativaly teiwnt to the aeuu cytopsthdot;ie sRat of thetK compounds.
IX. Gosrroinmrinol Tract
The use of hamsters in studies of areinojeaesis in the pstsointestinal
tract is still limited. In his 1971 Maude Abbott Lecture on experimentally
induced gastric adenocarcinomas, SmvnRT (ltlj mentions haauters as being
susceptible to pstrie sarcoetas when treated with Nmetbyl-N'oitro-N-
nitrosoluanidine, and Huuut (71. 721 reported squamous all carcinomas
of the foratomach in a large puaataSt of hamsters treated with NMU.
Dttu PottrA (261 induced forestomach cancer (as well as a variety of eeo-
plasms in other organs) by gastric isutillation of MC. Huutot.D (66), using
NbfU. on the other band found many neoplasms of the small and large
intestines, but reported no gastric cancers. DvM-w and SKtErs (331 placed
external strictures on the esophagus, instilled BP in DMSO, and induced
arcinortus of the forestomach and esophagus.
Since neither HlnAtu nor Srewnttf IpeciAa the genetic background of
the hamsters used, it is impossible to know whether these differences are
due to the different carcinogens used or to the different susaptibilities of
the animals. In view of our own observations'(79) of randotnbred hamsters
showing no pstrointestinal ancers after MC feeding, and as many as 65%
of colonic anccrs in mala of the BIO 17.20 inbred strain occurring with
the same ttcatment, and in view of the fact that out latest experiments We
shown that 4 out of 20 tested inbred hamster lines were susceptible to MC
adenoareinoma inductfoa in the glandular stomach (78), the importance
of hereditary predisposition cannot be overemphasized. Another example
of contradictory results obtained with eomparable carcinogen regimens in
different hamsters is the absence of any pstroiatestioal tumors noted by
I
I
I
6.r i f'"+ I-IN 042720
Chsmieal Carano,eneais in Syri.n Flamsten IS1
i
i
i
colony. The observations on thess tumon deaeribsd in this poper suaest the possibaiq
of using (LDH) and (C-6PD) isansymt analysis in distinguishing c)ininlly between
hortnonedependent and hormoneindspsndent eenal tumon.
Dooct and K/ra[M.M (29): Studies using a transplanted, suroWeinduoed kidney
tuawr, which alrer 77 transplam gencrations had betoms autonomous, showed that dur
inp tumorij*cnesis the expression of plucoss bphosphats dshydrojenau Quctwtp.
HA+watot, er d. (}I): One group o(mtk Syrian easntsrn rtasi.+d DES a.er a period
of 9 months. All developed widespread and asws renal twaora. Anot)rr itroup of aaak
Syrian hanuten was given DES plus 2 msehuwulfaoats (C813t)
oar the ame period. Thas hamsten either did na develop renal tuteon or 6ad rasu)
tumors that srs minimal in sevsrity. DES tr.atmast leduoed hyperpLstie ead oeoplaftie
changes in the intermedLts bbs of the pituitary Slards of treaud anima6, ina.uat tbs
number of prolaetin-rr-ntins alls, a;4 dets.ased the number of sontetovopinisotttins
aUt. Adding C8131 sipfibetat)y inhibited tltou changes iti the pituitary gland. Hiuo
pathologic and ultrastruetural aaminatiom indiated that the renal tumon .w eav-
t;inoeus onginating from tbe proaimtal soavoluted tubu)si
Kuw rr .l. (t9): 7A's p.pa rsvie.a work on the binding of (i,1'H) estrad'aI to
bormons responsive asd unraponwvs tumors. This has been arrisd out oa DMBA-
induoed rat aummary adenoareinomat, atropd+oindueed h.nuter kidney tumors and
saontaneout, pr*gnaneydependent mammary tumors in 8R{ mice. The binding of euus-
diol in tress tumors is similar to that in tJss uunr. The hormone uerapondve tumon
bind less hormone than do the responsive tunwra.le the rat mammary tumor, this appan
to be due to a loss o(cytoptatmio rsaptor protein but in the hamster kidnsy tueror, the
low binding !s .iw may be due to bts of throafatie tiaaptor aius for the estrndiol-
esaptor eompki entering from the tytoplavn AworkinS hypothesis is presented that h
compatible with both the binding data and tds other bioehemitil resulti obtaierd ttrM
these tumors. (Authors' abetnaJ
Ktanwu+ (90): A list of spontartsots t.nrl wtnon asd otavtenoeots and putiNly
autonomous dcrivatives of atroSsn-inductd n;nal esrsinontis of Syrita lusnuen is
peeaued. More detL)ed deeiptions of s new apontsneoa rsoal areinana and of attvee
'autonomous' dvivativa of suro{en4epsndmt teral areieoassa, all of which an avai4
able in a Liquid nitropcn wma benk, an induded. Although aadropen inhibits estropes
tumoripeneses in the Syrian barneta kidney, it nn be substitwed waessfully for sterotien
in maintainint powtb of arfy Iraroplant aaia) pasapa. Ie aueh transplants hor+na+s
dependency is .suaur lou between the 12th and 20sD aral pmatw (automm~y). These
autonomous derivatives of hormonedepsetdent nenol tumoA rwin respoeuivenrf to
soms stvoidal hormoew to varyin{ ane++ta. None of thent Aas bw as samphWy uuooo-
mous, i.e., hormor uneespoesive, aa ths renal areisotna of 'apontantous' oriSia AM
though removal of hormonal support from early transplants of this tumor may iMibit or
pesvsrit tuenor cell divisioe4 it does not ttioasarily pTSvent edl ttrvivaL A single tner
plant of one of thae autonomous renal tL+nors may sahibq .ery ntarked b<stologial dif-
ferenas durinS itf kJs lustory. T'hex diRsratt:a reAsd an aetia+ of ths host upon the
ne.oplasm and do not indrate projrcaion. Hosts for autonomous renal tumors may show
atrophic testes but rclattvely normal aoaeasoriet, suggesting that the transplant may trn.
theiiss phyriolokically active x uoroids.' Proprasion frorn hormone Jeptnlency to
autonomy in scrial puujes of the atroScn-induad renal nrcinoma oacvn fooUy,
1
{..r r/ R. 1 N 0f iwv M-22.I.
i
Howautota
IJf
resulting in all areas with varying degrees of hormone dependency within singktrans.
plants and stressing the desirability of using cloned material for is .ico as .ell as in nrro
transplantation studies. The demonstration of spaciik atro6an r.xptor proteins in the
hinuter kidney doa not eaplain the relation of esuopdt to wesor indunion or the hor
mone ratensi.eness of the neoptasm The roles of roaptoes, of stronuspithetium rsla-
tionships. of viral ponomes, of hnmunoldtieitY, and nntyenio differences in the induction
of this tumor and in iu proQeoioe from hormone dependency to autonomr aro still not
underuood.
K/aKMAM and BAcoY (91j:Of 12 QYIC himfleR, inJeLled WblUtaneouslr on alteTate
days .uh 0.6 mt or DES in the forrn of mieroerystah nnPe'rsded in saline solution. for
from 320 to 196 da)s, biiateral, sudanophilie, ronat adcnomes oaurrad in 7, and adeno-
arcinomas in 3 individuais. Ten maksa treaud fot W160 days developed no renal turnors;
neither did 14 eomparably treated femaks,lf untreated femala nor 30 untreated males.
The tumors appear to arise from a aasrow band of sudanopAilic epithelial alls near the
renal peivie rim. A similar band ooarn in feme4s. From thu band, in trsated nules onir,
cords bud outward into the adjaant renal eorta. DiRaent tuma nusres are well dcRned
but not eneap.ubtcJ, vary greatly in aiae and spreaJ by contact and inviuon. Csmuoty
separate metastasa nur oaw from diaphragm to.aotum. The lunwrs consist primuiiy
of intricate masses of bnnd+inR anastomosinj eords.aryind from I to 20 or mors cuboi-
dal calls In .ridth, and aunoueded by biood apt7kries otsd a.ery delicate network of
rrtim+lar and eoliapnaa Obat Maar taimttee ooar. Adenomts trry contain larp
t>teraie areas, or large a.ities 81iedwitb ehar. ndaasdaeopAtlic lluid. Within oords then
are few fr.e surfaoa. More a ksss aarotio aW etaia intr.ritalty with trypen blue and
freouently eonuin n.n, h»line dropleb eltaraeta<issie o( tioealksd 'wUoid det3, atioa'.
Meusuasas retain Ne aechis.etw+e of tbe primarry Wnar. ~
i..cowau and Gsudbw (fi1: Hep.tie dudaonAnnsfaase activity toward DES
deeaased in hamsurn trs.tad eAroeically witA DES (7.3 and 7 owtuAs). The pr.u+w of
both primitiv. atropendependent Aeai ttamots and traMpiuued tatro{cn-independent
tumors resulted in an increase of gluewoerltr.nsferase aa)vity toawd DES. This aaivity
was hi6hn in the hamster kidney Was in the rat kMney. t2ronie adnvnistratan of DES
dimethyl ether produord renai tumors in the anale hampar sindlu to tho+e produced by
DES, although a longer period of ueatman rto requir.d. DES nronot;lucuronido admind istered for Is
months diJ noe produce renal ttnnorf. Hep.eie biduewonidase activity
towards DES monotiuarronide .as not ieduad ia Aanwen trnted ritA DES mono-
glueuronide. Hep.ue O-dancMyius anivity toward DES dimethyl etAa was not induced
in hamsters treated with DES dinrthyl eUrr. Taii activity was aat erodi6ed by tee
pssena of a rasai tumor. (Autbors'.barau.)
1.etouttw.u .r d. (101): Fjtropn.depsadsnt ssnaW adenonrdnoma and normal
proaimal lubuia of tAe hamster kidney saAibit rynetional diRersnaes. Although both cell
types possess pp junarons, the neoplastie cells have in addition a eytoplasmic conRNra
tioa of ppyumior+ei membrane (anntJar natses) tat fouad in the kidneys of untreated
or estrofenimd hanrtan or in the nontumorou kidney adjacent to the adenoareinoma.
The presence of tJKsa unipue strwdues in the renal tumor and its abdominal metastases
was demonstrsted by el.cvon microseopp.ritA the use of 4nthanwn impnepaauon. A pos-
sible eortsiation tsee.wea thae stnetura and the atro'en seeuitiniq of tM kidney neo-
piassn i1 nnds.
CT R H N 0 4 2 7 2-2
i
Cteedal Carcinopcnais in Syrian Hamsters 139
i
LL er.l. (1071: Linear suerose gradient analysa reveal that all estro{co.induoed and
41epcndent primary renal tumor cytowls examined contain an t S and variable anqunta
of 4 S recsptor in low ionic buRer concsntratiom Similar results wers obtained with
auscts of primary meususes of these tumors. SutTose Sradicnts containing high nlt
(0.1 w Kta) convert the t S receptor in both the hamuer renal tumor and uurus to a 4 to
3 S complex. Scatchard plot analysis reveals that the renal tumor eyocsol etndrol-r.ocptoe
complex has a K, of J.7 10 w' and 9.2 x 10,' binding aita. Compeuwon for the tri-
tiated 17aestndiol binding sites in the renal tumm w aimJar to Wr i. the uuns
s.iM respsq to stroSenic compounds. Nonatropenic sNepids esAib.M nini+nal Oprn.
petition at the same eeneentntions or hiSha+. Substitution in the rin{ seryatst, par
tisylarly in position 3 of the phenolic A-rinS. resulted in a oonsidenbM len in the ahility
of such compounds to compete for thae rsrspton. Antiatrogent we sRstiva onm.
petitors for these estrogen rscepton only at higher eonesneratioru tsiauve so the truiate+d
stradiol
1,t.owwtt.Doscm and hrcao (I 111: A ee+ approach, anpbying hsescfrrnieal and
ekctron'Tksoscopic techniques as uscd in an attempt to obtain a mors tompkte ktww-
kdpc of atrogen-induad kidney tumor in the Solden hannter (CH). T1trs eurogen deriv-
atives, dinhylstilbatroi (DES). diethyWilOavol monotfucwonidt (DESG %), and di.
methyl ether (DESDAtE).were used on nor>astrotsd male hsasun. DES had the hrShest
Incidence of tumor induction (69':% of the animab) which is atsoedat.d with other tumors
(epdidyrtul and Nepatic adcaomas); DESDME induced tersron in )1`%, aed aooAra
plastic changes could be observed in the DESCAdatOaiattto group.
HiutoloSiolly, t)Ya main types of uruetura .ere asen which mi{ht be present ie
the same tumor: solidblastemal, mors tubularepithelial and papiltaryayuic areai?ltese
kidneys also had a plurieentrie tubutar dyspl+w and an interstitial ee11 hyee plarJa. A his-
tocNemial study of the embryonic metanephroe and tM intaruftial odY af nev twm GH
kidney, when compared to the DESinduesd kidney tumor and the OysOtauis taretumaal
foci, showed marked similaritia betwoat the entyrna present. The cernporuivs ultra.
structural analysa of the embryoeic deveiopirg kidney and the tutror Wtlf yorLds furUnr
undence of an rnteruitial origin of tlr neop4sia, trhidt has a pDorly dJysrstiaud and
diaud cell structure.
TM esuotee,-induad CH kidney tumor ti+ay wdt Oe(;in in the i.neaninl tsih of the
rsidwl meuncphric tn.ue in the kidney stroma.
Mcl.woMU>m rr ed. (I 13): Immunasuppresioa and tu.nor tsnsp(antu,a ncMit{us
were used to study the antipenioty of an suo{sn.detx*deat rvul tanw i..tusd han+.
s:crs. Neonatal thymectomy and chronic cortisone treatment whidr prodte d~dlrieecia
in csll.mnliated immunity and humoral antibody produetion failcd to s>to utra growth
signifkantly. Prior immuniatfoa with .iable ernor isografu did sme txets~ arumsls
apinst subsequent rechallenpe with 10' isoloillous tumor odd. I(ewlu sttgliese a tlswoa
tion betr.en hornwsul dependence and tumor imnwewtaenietiry.
Mrrtua (Il6): The presented identi(lalioe af taeqabolir with hessidieae swcture
uronply supports the view that epaaidatiat d tths st0bens double bond recueao a mUar
patMny of DES metabolis+n The epo:ids intermsdiatt would have to be eon+O&ted a
reactive metabohu and may osll be related to the arsino{eerc pountisl of DES. Ie addi.
tion, the poaible toaicolotiinl hssard ssaned by the formation or aucAal dernati.a
has to be taken into aaount.
~
. ~
L..~ 9 i"'! i 1 i 7 S..rr'""~" .~ '~ 2 1
How.uacnt
160
MuaTtn and Russru>.o (123): Suotinaa, auoo~siphoiplsate, b.hydroxybuqrate
and hoctitrate dehydrolenasa wertt studied !n a kidney tunror induoed by 20 m1 DFS
pcIIW given every 2 months to nnle Syri.n hmrrren for 1 rnoeths. The tumor was a
benign tubular adenonu. tnd staininl for rueanata aed ahydropbvtyratt dchydrole.
asses was abient is turoor tinw, whaqt auininl for Ilueoseiphosphau and 'nociuste
dehydrqenow was morr iatense in the Moplutfe thae i the sormal odta
X/I. Urinory Bladdet
Spontaneous bladder cancer in Syrian hamsters is extremely rare (It9).
So and WrtcDcR (176) reported the induction of bladder cancer following
weekly s.c. injections of 100 m`/kj body wtight of 3.2'-dimethyl4-amino-
biphenyl. The total dose neeessary to achie.Y this was 2,100-2,300 mBlkF
body weight and the earliest bladder tumors appeared between 181 and
257 days. Scventy-five percent of the hamsters surviving more than 158 days
developed bladder cancer. Mammary cancers, or malignant lymphoma, an-
cer of the wloe, and a skin arrinoma wen also induced. Prior to this, only
1!: 2-uaphthylamine given in food was known to induce ancer of the
bladder in Syrian hamsters (139J1
ln spite of the faa that damsun aerete as much as 20% of i.p. ad-
ministered AAF (2-IcetylaminoAuorene) in the urine in the form of N-
hydroxy-2aatylaminoAuorene, which appears to be the proximal arrino-
Sen, no bladder cancer has been obsenvd following AAF administration
(193). Orwsu tr al. (128) observed that a ttynthetie diet containing 0.06":
AAF and 1.6!; indole fo)lowinj 3 tinta weekly i.p. injection of AAF from
birth to weaning of S mg/100 a body wtijht caused bladder cancer in tall of
the treated animals. Untfeated controls were not included in this study
because extensive previous experience with the same hamsters by others
had revealed normal bladders. la another tnortt teant paper, OrASU er cl.
(126) studied the eRecu of indole alone and with two concentrations of AAF
given i.p. With the lower oonantration, a elesr areinogenic effect was
demonstrable. In some animals teoei%inS indole or tryptophan, only, and
in 2 untreated controls, there were scattered foci of urinary bladder in-
t'lammatioa. No parasites w,ere found in any of the bladders. The same
authors observed that iatratrscheal instillation of 2-acetylaminoAuorene
caused arcinoma of the bladder in hamsters (127).
N-Butyi-N-(a-hydroxybutyl)nittosamine in the drinking water also
caused bladder ancer but with lower incidences than those observed in W ista r
rsts (a2). Other substances ausinj transitioaal txll arcinorna in hamster
(-, f R f f N 0'""i' 2724
i '
A1
Ctemieal CarcinoSsnais in Syrian Hamuers 161
bladders were N(d-(S-nitro-2-furyJ)-2thiazolyl) formamide, N-(4-(S-nitro-
2-furyl).2-thiazolylJ acetarnide, formic acid 2-(4-(S-nitroa2-turyl)-2thiuolyl)
hydrazide (20] and levodopa (3,4-dihydro:yphenylL-alanine) (21J.
Homauactth er ol. (81] confirmed SAI'floTn's (139) earlier work on the
effects on the urinary bladder of administering a-naphthylamint in the
diet and observed marked differences in nsponsiveness between inbred
Gnes, some being resistant and others susaptibte to this form of ar-
dno8enesii.
ScGiiroiano Aormoiobi,nn was introduced into Syrian haeuters by inr
mersing the rodents into water infested with oetariae of S. hxmorobiwn.
In a large percentage of the animals thers ensued hyperplasia and meuplssis
of the urothelium (3S]. Others had demonstrated that inteetioe with S. hoe-
matobrum act: as a powertuJ cocardnoSen for e-aminoazotoluene (AAT)
given in the diet (68].
/" Caorr and Dnv.M 120J: N-(L{Nitro-2duryt}2-lhiasolyt) fonnunide (FANFT), N-
(6{S-nitroa2dur) I}2-tAfazolylJ acetamide (NFTA), or formfe acid 2-(1.{S.nitraMuryU-2-
tA+atolylJ hydruine (FNT). ootent an:ieoaens for the rat mot+tm and dof..as red at
0.1 .i of the din to nule wonlinp Syrian aoldsn 6nmttset ror u.eelu, followed by eon-
trol diet for an additional 22 weeks. The b+c+dent:r of tumon .ers: fANFT. 27 of 2d
hamsters with urinary bladder traniitional oreieoeur, S of 34 .ith fore:<om.ch spw-
tnouw cell papillonus, and 1or 24 with an adrenal aderoma; NFTA. 16 o124 hanrtas
with urinary bladder tronsitional a0 arcinanaa. I or 26 with aa adrenal adenoo+a and
I of 24 with an adrenal adenoenrcinoma; FNT. 9 of 34 hanrters with tK'vury bladder
trnnsitional eell arsinonus, t) of 24 rith tonstanaef :hrlnots ed1 peplbmas,
6 of 24 with adrenal adenomas, and I of 2a witb a renal tsttsitientd ail arsi.
nomi Only I adrenal adenona was fotn+d is vs untreated hamsters. Tbns bta
ds+nonstrats that hamstas art aa t+tseetpibie a otler t+pciss oe ths artaneaenieify, of
S-nivofuranL
Caoer st .l. (211: Isrodopa O,~d~-.Ianiesl w1s fed at I.tl'K af the
diet to 60 mals .Kanlina STrian golden hunors for Ia auk1, folb.~ed by control diet
for an additional 38 w.als. The incidatea of tuean were: 3 of 10 hatmtsn with rotF
stomaeh sqwenow all pspil1onmas, 1 of 60 vith hyotayosaeeoma of the skis, and I of 69
with conical adrenal adenoe+s. Two or 20 eontrol animak derelopsd adrenal ada+omea.
Hyr+vplasia of the rrinary bladder spiUteliwm ooarred in 33 of the uated aroup, and
hytwplaw was na found in ths bladders of ths ooarol pouo-
Ea.-Moas+ If.l. (3SJ: The aien of this study was to iMua apaime+tal asbiuo.on+ir
ais of the urinary bladder throuah a wtural routs ot infsnion is hanrters using Seiiu.-
aonr 4o.maearott. Schiuowmal cyttitia was ptrodumd in I I ef 18 aAint+lt~ Ia i animals
there .ers epithelial dunees, hn+erplaw oMy i.1, a.d bedt bypsrplaaia and squamous
meuplaua in 4 animale Two lornr s+f pwetan metaptq%io were soat, a+e sutwdadna
'. that which dsstotw in the urit+ary bLaJdcr of man and looks Gle epiderntis, the other
eonsetine or many loycn of aaive basat eells with 2-3 layers of Aattsned cells en tlr sur-
face. A%,cloprrkrt of rQuanwus muaplatia is panla+tarty intereuinp since it 'ts e+on-
tidcred a preanarous ks+on.
CTR HN 04~.%-2~
HarpuRCn
U
Hicy er bf. (tit1: A nusal tslationship between Schliroaowr benrroAiern and bjod.
dv oncer,lSru suggested by Ft:acwow (1. Path. Hact. Ii: 7i-94. 1911 J, has not yet been
taablishcd. In some endemic artw it mty, howevsr. have important public hcilth tigniA&
nnee. as more pcople suRer from bladder nnnr and S. ik.roser.b4m infenion than froen
bladder nnnr alone.
In our experience the parasitie infeotion does not produce ,n+alipunt ehantp in the
bladders of either baboons or hamsten. The folbwing esperiercnt was thaefore under.
taken to determine rhetha an esopenoue nreiaopes introdund as a t:adaetar to the
infeaion .ould IriR,er tumor fanution. .
Three hundrad hamsten were divided into six Foupt. atu:h of 30 harroters. Thne of
thae groups were acb infected with 10 SL i.enwoNww oerearine (Egyptian strain). Ten
weeks afux infenion aeminentaoluene (AAT) was Introduced into the diet at leveb of
0.1 and 0.0:/% in one infected and one oninfecteJ Eroup, t+etpot:tively. Taunt. Dcuw
MnTn ond SHwR (CuKa Ra. 2/: 1313-1317, 19N) cbo.~ed that 0.1% of AAT in tbe
diet produced tuewrs of the btadda after 49 .skt in 45% of the hamuen.
One hamper from each Sroup was anerified 3 tnotuhtafter be3innhy of the nreinoaee
tratment, and thereafter one every t weki. The bladders were B.ed in formalin for hutol.
oV. the infsa.d hamsurs.as ptefwed, aMworm and tipue ea oeuots.ers earried out.
TTs results ihowd that the normal pathoiop nuaed by tM eip ot S. Aoanuebrwn
deposited in the bladder nll ns be tiwyad 1o a te.lipnant ievaaive nreinonta in 24
.weks by inueduetion of AAT (0.1 % Mwp. TLe oeeieoree akaee tsund only hyper9tasia
of the epitheliuen, but no inraive {rowth.ithia tbie tktte. The 0.02% level, either abne
or together with the p.rasita, did not produn any iwnMa Qe.M ef epithdiun during the
54-w.ek e:perinwttal period.
Howevacn er .l. (f 11: /n 19i7, the only aooeptable method to daaa potentia!
human bladder nrcinopm was administntioa af urpeeled eeetpoutdl te btatle dop in
high eftt+trtrauons for at Ie.N 6 yaa (1rurYS: lbleier G.ea. Aoalapia hae,
llirminaham 1967/. At the tame eympositam. S.inoRTt teponed the mdutaien or
biaddet
nnnr with 1% d+uphah~lamine fed to taedombr+d Syriss tdden hanwers. It h ws-
pested that the usa of inbred lineti of !10 hunteri, espeeially aaaeptibk to urintry
bladder nreinopena'r in ropome to dietary ¢naphtAybnwtt. may pro+~ide a moee tcnsi-
tive nrthod. Croupt of 19J0 maka and I9-39 faeela of ase6 of 11 inbred !10 hamster
urains srs randomisd by weight and placed oa a diet of Ttrina claam containing 1/.
dnaphthylamine. The animah ..rs killed whan tnoribtrtd aud autopeiad with apecitl
attention being piren to the fo.nrlddtyde-iNlated arinary bladder. Thie prelintinary
repon deals with sis inbnd lines and one troup of ttindombnd anireuh. At kiaat 10 males
and 10 females in each group were eaamind Aiatolo`inlty. 7.7% tumora (I out or 13)
and 103% tumors (2 out of 19) .ere ttbtav.d in ma4 and fsnmle tsndotnbrod animals.
Low tumor ineidence+t also oonxred in inbred DIO linau: U9) (nrle only) and fD4. In
contrast. !10 7.88 had 40% tumors in maks and 61% in females; 810 1.5 had 105: in
nvlts and 41% in fennlai 110 15.16 revealed 7J% in tt+alet aad 41% ie femaha, and
'1017.20 yielJed 20!: in nnb and 16% in females. Tluati. animals (especiully females)
of thns lines are more susceptible than randombred animals. Ths,arlist tumors appearod
at 3d .+ets, the latest at 6/ seka Femak hanuters of susceptible lines are most rapon-
a'rve for detection of naphthylaminMype bladder nrcinoptxn, Eiriof ttatiuinlly valid
tesulu at nasonabk eost within 64 .ftks.
[.r f R f f f ] Sr1''%' 2726
1
... ~
L
taeminl Canrinopenesis in Syrian Harmten Ip
I
I
i
I
I
ho et.l. (/7J: The effeet of various factors on the development ot urinary bladJv
tumor in nts, /uine.t pits, and hamsters given NbutytN{LAydroaybutylptitrotamint
was eaamined histologically. The Meet of Ieit and ale, and of the dou and period of
administration of Nbut)lN.(i-hydroaybut)bnitrosamine on the int:idtne,n of urinary
bladdcr tuman in rats was also investigated.
No aei diRercnee wu found in the inadenoe of urinary bladder e.netr in na. How-
s.er, the incidena of eanon and of squamous maaplasi" is areas of anssrots titswl
was IrpUy innuenoed by the tys of animals, bein5 much Ifi+ha is older /fta Ilskn is
ywn/er rats.
For development of urinary blsdder anar in Isn, the ntieirtwns tarcinoSenie tbr
of NbutylN{t-hydro:;ybutyl)nitroumint given in tlte drinking water is 0.005% whiM
0.001% is the maaimum nonarrinopenie dose. On admuuuration of 0.1% oiei
no0t:n solution to nts, the mininwre period fsr tlr induniea of unnary bladder tanosr
is 1 weekL
Guints piSs tsnd hamsters sn lea wweptible tNan Vlrtuar wsia rnte to tse isdut
tioe of urinary bladder eanoa by NbusylN{4Aydroaybutyllnitrosamina
OrAsu.r d(126J: Hamsters trsated with 2..arylantinoAuors++e (AAF) sn ssudied
to tnt the eReets of dietary indole and esoat ottryptotthte and the initial aSe of tfr
aairnab on the devclopment of bladder tuteorn. Naonatal males and fanals we» Siven
Lp. injectione of AAF. S m5/100/ body.eilbt, 7 times wakly until ranin1.11tey..r.
then fed a synthetic din containing AAF .ritA or witAout 1.65: indo4 or 2.0% ok
tryptophtn. Enhanxment of tumorilerwis in the urinary bladder was evident only w6ea
indole was added to the diet sonuitunl a low dosn of AAF (0.0)Y.). Of 27 hamsan fed
the combination diet for 10 mont)u, 24 developed tnnns (19Y.): 20 of tAan .ere iarasim
On the other hand. 1] of 26 on sAt diet eontsiniu/ AAF alone developed bladder tumors
(50%); 1 of them were inrasirs. The diRereaoe in ineideecs waa signiliant (P4.01).
Development of bladder tumon .ppsand aGSfstly ddayoJ when older harnsun (initi.ny
4 weeks old) were used, but aftar 11 months aq nuinub developad blad~kr tumots Iu w
observed in rats, added indok or tryptophan proseet.d the 17.er from AAF injury and
Irntly reduced the dc.elopment of cholanpoareinomaL
Orsu.r a/. (127J: To de+amine if bladder tuewr: arm indumd by a kiw.m bladder
csrcvtolen rsnntsdly administered intrstraelrauy. asalint suspenuon of 2-aeetytatnino-
tluorene was instilleJ intratracheally imo young tn.h and fsmale 9ohleI hannters oea or
twios a.eek for 17 months. Of the sl ham.tars survivinl t months of trntment. 1/ devd-
oped bladder tunan. Thus aEsorptioe otarcinolee through the airw.ys rao uwJua bW-
du tumors J audt eapowrs is cootinwd for a lond tione
Or.w a.l. (121J: The elfeet on tht de.elo4meat of bladder twnors of s+tonalal
treatmcnt with 2-aoetylaminofluorsne (AAF) follo~.ed by prolorOid r.edin/ ts oombu+a-
tion h nh indole wos studied. Neonatal nula and femahs wsrs given wvspentomaJ iajae-
uons of AAF. S ml/1001 body weight. 3 times weekly unW wneinj Tbey.vy tlses fed
a synthetic diet eontainin/0.06.i AAF twd 1.6% endob. T!s 26 9aewtrs surviving 10-12
montM developed transitanal an careinomas of the bladder. .n but two of whicA .erm
invuis. No hamsters had malignant turtwn in the Grer. SMa Aansras developed pdioaa
of tAe.pla:n. (Authors' aburact)
S.ntvrtrn n al. /139J: Env;ronmental data on the type and duration ot exposure of
workers to various dre inurmediaw are presented. The ma)or sowce of aposure for
CTR 11N 0~~~;~`~ r
A 1
Howsuuctn 164
pnaDhthylamine (BNA), a-nuphthl9amine (ANA) and bentidine an aiven. Aclationshiet
betwen heavy mJ liaht eaposuw to 3NA and the ineidrnut of bttdder enlignanoet are
reported. ..
The ineidenoe of bladder ttulipuneie for vorten espotod to only one subsunee
w hiaAest for M- DyA espoud group and lo+ett ror thoae espoted to ANA eonumi.
ttated witk DN1» A dtent in tapome to 1NA rewlted in a sharp drop in the ineidonot
of bL4drJ taalipuneias among Y+o tas enPied in the atatufaettne of DNA. Hotiever,
the appedranoe of bladder tunan ia two tww .orkns who wsn enpoted only to DNA
durin= the period of light etyosun indiestr that this material can probably not be
Oronetwd tafdy unless a eoanpietdy ondowd aWemoted syttan is provided.
A jynenjistie eRect be:weat DNA and bsusidine 4 supested by the Bnding or the
hiahetl itKidenct: of bbdder nulianattciei* in the.orken espaeed to both of tha materials
eotnOaeed with the o-her groups of .otlurL
fo and Wn+oa (1)il: Set pap I!0.
Wttuuaeta.r.f. (1951: Thne 6+nontAoid male hantstsrs and thne amottahold
fenuk hatnsters er. given inttaporkonn! ittjeaioro of a suspension of N-2dluorenyl
f-"CGaceumide in i.otcni- wline aum acseia tolrtion at the kvel of !o tna'kS body
wviaht. The animals ws e,ssd singly and urina and teas.ere eolkcted separately. At the
end of 2 days t:xy ws killed and variout oryw were studied. Noteworthy is the pnr
dominana of the ronnuion and e+eeretioe of dueuroeie acid conjugates vrhicit ata dimi
naud dtielly in the ttraL ta this tesard tha hanaar It litts ahe Btwra M tttrtborstore,
the hannttt eamet twwtantiat amounet to tha Ndtydrot;p derfvsti.a This it thouaAt to
be a tteamsry nrubolisa whim may kad to tM active eateieoDea Tha rat Detrratly
fonn only un.u tnwirata oi tha tttetaboiita and in this rapect. the hatnaar tesembia the
dog. rabbit. ot aataey uW nnts. T1+e higher anteunt of protsinbound tadio.ai.ity in
tkR tstak t~.ataw. I oattpra/ :o that is the itmala hamatar, It ooaibty related to We
higher auotptibiLty ef the Gvw is the aaka.
XIlI. rroitot.
An attemp: wu made to iaduce prostatic cancer by Injections of
DMBA alone or in combitution with adeoovirtu type 12 into the dorsal
prostate of the hamster (192j. This was done in inuct males as well as
in castrates and in animals trated with testosterone or eestradiol. Only a
few sarcomas .rers induced in numbers too small for ttatistical signifianee.
The few rutnors that wcre induced did not taemble human prosutic
Carcinotssa.
Y.av.a.em w d. I t 921: The hutnut adasairut typ 12 and tha eAemid D M BA
inatilaud into the trowu of adult hamtten show tumoryenie eAecta only in the pres-
enoa ef etoarnoo adernstrat iee of etuaGiol or wtotatotte. The typo of tun,or ob.ervsd
.nt Oroautie tarcana, balf of which .en differentiated to nbraareoma. Castration did
not change the inodom of tM lesions. The pattan of hormonal inAuerw was related to
aoDa+aa suoBs rawr thas anaroDat depeedsttc7 `R'hat vinr or DMDA.eee admin-
Cf R f i f"f 042728
/ k
CTemiesl Grdnotenais in Syrian Hamsters IdS
itasd. Androgen dependency was round only in the prepena of DMDA. both ttinwli
toSether rbowd no potentiatinS ellen in inereasina p.ostatie twnor ineidcna. (Authors'
abstnct.)
XIV. Orory ond Thyroid
Tbe induction of areioomas of the ovary (mostly of the =ranuloa ed1
type) has been achieved with two or three wed;ly repeated injections o[
DMBA in 15% fat emulsion in 77-i3 % randombred Syrian hamsters 11841
Oral administration of MC in corn oil in si:t inbred strains of Syrian
hamsters yielded 20, 21, 25, 33 and 56% avarian tumors, respectively, in
each stnin studied (79J. In randombred animals, 30% ovarian tumors wttre
induced by MC feeding. Administration of utI and teethylthioucacil (MTU)
caused =rsnulosa cell tumors of the ovary (17, !E); MTU alone caused
adenomas of the thyroid.
CMaotvv and RNCwzv (17): Only adenomas of ths Myroid were found is anirnab
trat.d with MTU or with N'1 after 5 and 10 n+ontM, respacti.dy. Treatatau with both
",I and MW thoneeed the latetu period and tM at.ebrr of etrnon was arater tlus
that is miee and rata for the ame time period. "'! and MTU appiiad toSether led to tM
development of thyroid areinonw aftsr moes tLan f tnonths.'fhe indutsd tun+orn (benipt
and malidrtant) was principally of a patilliferar tyba Oa the haan of aM shonened
Iatent period for the development of thyroid aderansae and eareinomu and the greater
tumor frequency, hamsten ars ne+oarrKndd as a suitable etadd rar retarcs on Myroid
artino=enesia.
Guerrov and Rmcav (ItJ: The appearss+ae and tttrueture ef IJst trvariae Wmors
In hamqera tevad with uq and mahyUhioursu7 atoee or in.sanbimtio..ers audied.
Nodular oall prolifention and ttunor powth .vt obNrvad ia 90% of all "'lwtjeetad
animals kitied betwen the 600ttt and d20tD day after tAe bepanies ef the satKrimeeL
The inJuad tumoes were nu7nly of araetYota and granutoaaah.ea a!l type. DiRuae
hyperpiaiia of the ovarian 1 odb is .rtAylthiouraeil and in
sa+r
bined "'1 * nxthyltEiouraeil tr.amtsnt w eaed. TUe AipoSeeKs's of Ute osrian tumors
and the eRect of "'1 and metAylthitwrntA oe orarite oarciooWensia< is haewant wrt
discussed.
Horavncn er aL (7f): S.a pap 101.
Tont ll{IJ: Two or three wexkly repaat.d inawsnetn inja:tioear of DMiA Ia 13%
fat emulsion sre given to adult randomiybrsA Syrian aoldea Surr+en. The ueatnKeo
raulted in the induetion of orarias tumors is ti» fem.lea .it! inctidetnoi of 77 and IJ%
is tIK ttiria and th+.a tieui itjelcfad animah, rayeaireip. Out of the 1J ovarian tumors
found is the trsroted Pa+pe. 23 .vt the aranuion aU type, d.at the thea cell typa.
IS sre the =ranulotathw all type (miied) and I was a Aitar tU tumor. In 33 aaitnah
the tumors oocvrred bilaurally and in 10 ttnilateraly. Additionally. a significant persent
ape of animals of both sa.et devdoryed danul tndanoeriomat, tuewrs of fotaton>aet4
brt,ut, intestines, tkir4 slubcvtis, lymphorqicuLt tiuue, ete.
I
~
C..r ~~ f"~ f f >r ~ 042 *i' r- q
i
C
1
Ho.uuacut 166
The induction of ovarian tumors with high incidence by a td+smiot orcinogen fn
the hamster provides a model by which the tacton involved in t8e p.tboScersb or
Wit
ncoplasm eould be taudied. (Author's aatrset.)
XV. rwrrde,
Zinc chloride injected into the hamster testis caused embryonal' car-
cinoma (S2J.
Gunau and Gtirnas (J21: Zinc dJeridM .oiutien inj.etsd Into tM uua of
e Syrian Mmrtafs dwina the nriy spring tnontlr resulted in twe embryonU areinonu><
of the toti>t found at neeropty to.oeks ater. Tbe zinc cNxide injeetionaweee suds dur-
inS the period of rapd ttaa<onai Soasda! Sro.a6 whea apennaoSonial division is activated
and resulted in areas of eaguativs neare.ik eocupyinS about 23% of acb teui.. The
tumor aras adjaoent to the ae.aa of a.aai. -
zv/ Menunary crat4 racnW, Abamr
Subcutaneous adminiarstion of'9rethaA to the saekliaS hamster led to
nodular hyperplasia of the adreaal oocta and to adrenocortial tumors, with
occasional metutssa in tbom animals which survived more than 1 year.
The saine procedure k: to kca tumsr& of the pancreas. Subcutaneous
N.N'ditnethylaitroaourca caused ttmort+ of the forestom.cti, mammary
yand and uterus in adult hamuers j72J.
Feeding of MC by stomach tube (79J (see Howotrnetx, p. 103 caused
mammary cancer in nearly all females so treated in some inbred hamster
strains and in about half of the dosed raadombred and resistant inbred
animals.
2,2'-Dihydroxy-di-n-propylnitroumine caused high incidenca of pan-
erratic duct adenomas and ducul carcinomas, while otber derivatives were
ku efRective in this respect (144,147j.
MAYSUrAwA and SUZUKI (114J appear to have succeeded in inducing
adrenal tumors with subcutaneous iqjectiotu of urethane into unborn
'
hamsters.
HMua /72): S.e pop iN.
Ho.nuaaa ea.l. (79): Sre paS. 101.
MAtwvar. ud Susu¢t (I1)): SuekWy Syrian Soiden hamsters .w injected suby eutaneoutly w;th IoSi
r<aina.oiution of rnthan., at a dose of I mS/t of body Msiaht.
onoe a week for 6 weeks. The nitjarity of iM ttein+.h,.risieh wevi.ad more than 52 waa!<s.
derelop.d nodular hypepissia of tD. sdrwl eertet and of the oawutic ahu. EiNt
t
I
V" TR ! l l 0/ 2itI -3W'
C7rcmial Cardno9enais in Syrian Hantatat 167
adrenal eonial tumorn, indudieS two metattasitin{ oeKs..nd a bail tumor af the
pancreatic islcts uen also found in the 28 trsated hsawers. The hiaolM of the adrenal
lesions suitests that there are possible prodrasi.e steps frovn the hyperpiastic nodula to
the derelopment of the tumort.
hrtm .r al. (Iw): Weekly a,t: b+)tKtiotr of npuitoaie dow of Prydroayoropyl-w
propylnitrosamine, 2osopropyl-ra-propylnitraamine, and nKthyl+propylnitraatmine,
aswand metabolits of di.apropylnitroaamina by /.widatiot4 induad lowincideeoa ef
paneratio duct adatomas in Syriae golden hanwen dW net.
AOpliation or 2.2'dihydrerydir.otdqylnitraamina, anollrr poaulaud istnetn.dittt of
dkw popylnitrosandne. led to devdoperet of various tiroa of oana.atie duet ad~eoem
and ducul areinomas in hiSh perantaga o(banwers Ie addidon, a fsw aelnu a1 ar-
einorrw .ere found. The ttwrpholop of thtae neooiasnr, their lat,nciw, and their ditr
tripution in the JiRerent as nrnu ot IM oanatw an de.cibod.
Poua .r.l. (147): A high ineidt:net af pantitatio aeoplaunt urY induad Is Syrias
golden hartuters following tuEeutaneas applications of diisoprop.nolnitraamine (DIFN)
ona .+eekly for life. The tuma latsncy vu n Uroet as Is .y.ki. In dinial and a+or-
Olalope aspau /Ae Ltduad paneretie tumon e(oedr eusenbled thote of hweant.
RtJerrneet
I ALTHOFF. J.: Simultaneous tuntors i. ths rst;piratory trscsa+ and urinary eladdv of
Syrian golden hamettas. Z. Ktebfexsdt. 82: 133-IJI (1974).
2 ALTHOFF. 1.; Gaz" A.; rova, t. and Mowa, U.: Ctireseopnie dfst or N-
nitrotohaamethylenicniee in Syriu plden IwatrttA. J. aaen. Q car Itst. i0:
J23-)29(1973j.
3 ALTHOFF. J.; FaoM lr(L tnd Gwto+a.K C: Chrdnopsk aR.at ol J~,2'diatabyi.
dipropybdcroaer:na in Syrian haTaurf. J.11atn. Canea Intt. JJ: 120l-1211 (197J).
4 At.itoon. 1.; KaUCtt+t, F.W. and Mowa, U.: Greitaganie.tfaet of dipreqinhret-
umine and oompoa+ds ttdaud by Foaidatioa J. trta. Canar last. Jl: 2J7-2111
(1973).
! ALTHOFF. J.; KaOota, F.W.; }luascK J.; SearLt. D., and Mawa, U.: Cusino-
{snicity of ¢Aydro:ylat.d diptop7laittoaaeina. Whr+rstsardtaftea 60: ss (197J).
S At.nan, J.; Kat3cat, F. W.; Maa, U., ud SewLu, D.: Dibuwrlnitroamine
ardnogertsia is Syri.. Soides and Chieaa hsesae>t rroe. Soa.apL tiol. M.J. IJM:
)til-17) (1971).
7 Ar.nan, J.; Potm, P.; C.aco., A. and tr/au, U.: Cornp.rsuw audies of .s
p4stic rsponsm to S w+ile do.a of nttrow tompounds. 1. Tir dlea of N-eiuu-
sohesamahyknsiatie. in Syrian S,olden hamsaas a+d S.+n twes. 2: KieEsforseJL 78:
7F-f 1 (1972).
t At.rnors, J.; Wu.eoM, T.; C.:ota~ A., and 9otn, P.: Compamive studia or naa
piastie ra9oese to a single dow of aicroso compounds. 3. The dl'ect of N-aitroso.
ppsridine and N-nittoaomorpholine in Syrian golden hantstert Z Krstsfoexh. f/:
231-239 (1974).
9 ALTHOFF. J.; Wwo«, R., and MaKa, U.: Diethylnitronmin.-induad alterstioa
(..r TR { { N 0`"Y' 2f~ ..~~ 1
ta
Howrau.ca
/1
Ip
in the tracheosronchial cyftnn of Srritn =olden hanuters. J. nun, Gnar Inu.vd:
1067-1071 (1971). '
10 Au.cttr, C.; P.wR M. ct fouutw, C.: ERet dr 4 pnblaeiomie wr ki tueKurn
mcbnipua du lunwa dorf inJuita lor )'adminiwstioe f'er.tJ d'une seuk do-A
de 9. I0-dimlthyl 1,2benaanthraolne. CC r. Ae{rd. Stttne. Aad. Sei- P.ria /: 271-271
(1970).
11 AvncaT, C.; htiot, M. et loatuou. C.: TunKws wv24nqsa td7es Is hamster dord
par I'administrition Frr ot d'une seule das d. 9,IOdiRt4hyb1,2hensanthrac*w.
Annls Dorm. Syph.90: 313-3J1(1971).
12 8cu.ran. I. and How.utratta, F.: HiSh nieotine tola.nee ef Syri.n Solden han»ten.
Tosic. appl. tAarmac.22: 324 (1972).
13 lrewrct,a, F.: Hnwatmota. F., tutd Rttsttuo, A.1.: Str.in differences in the
raponse of inbred Syrian hanrtat to eepreue anwhe iaMbtion. J. nate. Cancer
Inst. JJ: 1111-1137 (197!).
14 lw.a.oWA), V. t. and Ltmttt.. U. K.: Atid {hotphawe and deozyribonucleic acid
studies in oM eA mduced eaperimental or.l eereinoaeemsis in ham.ter ehech pouch.
Indian J. med. Res. J9: 401-412 (1971).
13 D.owr4 1.M.: The effect of acute X-irradiation on the es11 proliferation kinetics of
Indueed carcinomas and their normttl pounlerO.n. Rtdiatt. Ret IJ: i27-63) (1970).
16 CAUrrut, H.: Call.m.diated immunity to ters) .r)ilprtsndee in lwmam and !sti-
tNSn. ar. n+.d. J. b: 701-'A3 (197p.
17 Grastov, K. and R.><wtv, R.: TAyroid otehroSertasit In Aunter, aMr trnttstent
ritA 1Jl:edia and methyllhiourscil. Z. KrebfoeYdt. 77: 171-179 (1972).
18 Grusrov, K. and R.rcwa, R.: Frolifer>tt).e and tseopituie ch.nptr in the ovaria
of hanwers tr.atad rith I11iodirr atd tanhyltaiouraciL Neoplawns 20: 31)-3)f
(1973).
19 C+tV, E W. and M.ureatn+, LA.: Ati hthfSitotY eR.et ef vitamio A on the indut:
tion of 1un+on of foreton+uit and tsrvis in the Syr4. Aaewet by arcirwpenic
po)yeydie hydrocarpont. Cancer Rea.1J: ti4i93 (If61).
20 Cttoet, W.A. and Sav.M, G.T.: Production of urin.ry bladder areinonus in mak
hamsters by tw(a{S-f+iuo-2duryI}24hiamly() formamide, N-µ{3-nitro-2duryI).2.
thitwolyt}usumwJe, or formic acid 2-µ(Saitror2-furyl}2-tAiatolyll hrdru+de. J.
Mta Canar Inst. Jl: 9r1-9r9 (1973).
21 Cao.r, W.A.; Sar..A, J.L, and 11!arar+: G.T.: Urinery bladda eRacu of kvodop.
In Mextert. Arcfu hth. 99: 471473 (1973).
22 Dect,orrat, F. and Mttvrma. M.: Asedye binding to proaans and detosintion of
p4imethylamtnaaabcnanK in a+ouw and Oanuter (ivv. IAL J. Canar f: NI-U7
(1970).
23 oeKtaMro.w, J.3.: Rowa. M.L, and hMr, L: Gro.th inhibition by t:hemo-
therapeutie apw of ui)hatroknduad lenatar l;dney tumor. SurS. Forum 22:
sld-316(1971).
24 Oeuavt, J.; Mtoror. J.; CAtntT, T.; Dtaota. J.: Canuntt, J. F.: Rerwts. M.
a iueK J.: Vaadarisation et esoiu.na tueronte ar otwrs de 4 esrenoeenee
tAimipue de I. OoNr NPh du hamste doH. Etude yu )a mlthode d'intanions
vaswlous et de raenuwution firaphipue a plauiquc. C r. Sdanc. Soe. iwL IdJ:
991-1000(1971~
CTR ~~N 042732
Clwnial Careiaopenesiu in Syrian Haatstera 10
23 DtuUt, J.; Mtowar, J.; Duaota, l.t C..nu.tat. 1.1t. a Rtn+d, M.: ModiRc2-
liotu vaswfaira aecompaanant Is naissancs da arcinmttes eaplrimentalemcnt po-
voQuds danf Is pochc jupk du hamster dorl. C. r. Seanc. Soe. Bool.16J: 1001-1003
(1971).
26 Duu FOat.. G.: Induction of intes<tinal. munmary. anf ersrian tumon in ham
aten with oral administration of 20-methylcholanthnna. Casoer Res. 21: 373-379
(1971).
27 Dt r.oto, J.A.: NuMow, R.t, and Doww.N, P.1.: anr.aaatio ef printary
tumon indueed by arcinogenic polyeyNic hydroarEona ira Syri.e hamsters. J.
Sytn. Cancer Inct.I6: 171-It1 (1971).
21 Dama, A. H.: Fstropn.depatdent and inde}veatdent tenal tw.ers Oneebpp !l:
253-239 (1973).
29 Dooot, A.H. and Kaiw.w, H.: Glaeote LphotpAate dehydraJenae 1e pimary
and autonotaw esu+ofaenminduad eenal tuewn of the Syrian kanwer. J. Cell Biot.
47: 31a (1970).
30 Dor+mvAt.L. W.: Faperimeatal btvestiptioea on the eReet of e+pree:e uneke
inluluion on annll laboratory anienala; in H.w+a. NMtaMtu. and Gu.uaT Inhala-
tion esreino{enesit. AEC Symposium Series No. 1{ (CONF891JOt), p.3t9J12
(USAEC Technical )nfonnation CeAter. Oak Rdge 1970).
31 Doxrorwtu., W.; Gt[v.uu, H.1.; HAttxA H.r.; lAu.ba, U.; Rmstae, G, tta.
SatMUOte. B.: lnvestiptioau en the eRecu ot chronie eiSarau.nroke inhalation
in Syrian gotden Aamttera. J. nitn. Canoer Inst. $1: 17i1-1112 (19TI).
32 Datw, R.T.; Lascn+, S.; Ktsaau, M., and Nsuow, N.: InAa)atioe ealeino
genictity of alpha halo ethers. L The aeute inAalation toaidty d eAteron+stDyl ntethyl
aher and Ois(chloronYthyl)ether. ArcM aw'v. HUA J0: 61-H (1973).
33 Duw++.r, L1. and Swesu, R.H.: Effects o(aophagtal oenuraiou an Omm(a)py-
mne areinot)et+eais in hamster e.ophapr and faestom.dt. J. au. Cauotr lat. J):
t7S-8111(1971).
34 Duww.a. LJ.; SMtslst, R.H., and Moara+. J.1t.: troliferaiw leaiene in eMek
pouch and nopu6se of Aaanters tnatad with plants froo Cerua., Nctlieriaadt
Aatilla. J. natn. Cancer Inst. JJ: 12ff-1269 (1971).
13 EL-MOw. B.; Stau>, M.. and Ea.Rwa. E.3.: Esperimaraal wlltar:ial aqwmots
ttiesaplasia of Ur tuinary btadtkr in dsmuuL Etar. J. Caaav ll: I99-201 (1974
16 E.ro..oro. M.; Mrvazs, M, and S.ro, )C: Garesovnieiq is thft hamster of einwl-
taneously admin'sur.d 2-.aewnidoAuorens u+d 3-a+etAylcAaia.tit..a. GaaN 19:
177-166 (196/).
37 Fuo". V.1.: Rapiratory ttset tumteea in hannurs aJur ietratruieol waullatioa of
lenco(a)pyrene atonm and fwfural. Canov Res. JJ: 29-u (H7Ti
)1 FtaoN, V.1.: DeJow. D.. and Errttwr, P.: I.anes to eb .t+:er: row+apoeu>t
correlation for the indutuoa o(retp'tratary.uaet wtoon i. Syrna Solden hanrtert
by intntrsd+oa) iew7buas oI bentae(a)pnsna. Eur. J. Catwr 9: 3t7J9o (197n.
39 Fuo.ti V.1.; Ewa.rt, F., and Vowu.Aa, T.: Louer teqirnery uset turnoun ie
Syrian Solden lumcters aner inastradral inuillatioro of Jiett)Yt.uoaamuis alone
and with ferric ocide. Eur. J. Cancer l: 113-e.9 (I9?2).
40 Fu+qr+M, S. L and Gauxa. G. W: jr.: Cytolotic chan,a dwing noey++nul nr
c;noSenan. Acta cytol 10: 219-293 (1946).
CTR HN 042733
Hoauvnata
170
41 Fa..cuv, C. D.: Mory+hometric quantitation orepltMlial nudare7teplumic ptio~
in aperimentat oral anan0Vnrsus. J. dent. Ra. JJ: wppi» pp. 1062 (197e).
42 FwtTti K.; KACU. T.: S".et. M, and Qwoc. T.: Esperimental produnion of
lir,pwl nreinpmas in Aamslers by loeal applieation ef 9.14diertltyl.1.2benun.
tMacane. J. der1.1(a. 3!: 327-332 (1f73).
43 Fuast, A. and t:Atf>m,t. D.: F.ilws of tdne to tKpta CnOntitttn aranodensis.
Absir. No. 248. 14oe. Am. Au. Canaer RaL lJ: 62 (19721.
44 Fuasr. A, and SeMUVUa. M.C.: The Aamr.ur aa s ewdel for erul eaneinotenesis.
Proc.wtat. pharnacot. Soe.1t: W71 (1971).
43 Geu.YA, J. L: Rur, A.E. and Sewa. G.:1sellius Gtmnte-Gu6rin and antilrme pboeyu sertan in
oreitwfenaie. AreM htA. U: 2)7-240 (197q.
46 Gtur.r., J. L and SNtctwt, O.: TUe eRat of aatilympAocyu unrm en esaerimenul
ttamua buaal poueh aueinofenasa. Onl. SurS. Jl: 301-3l7 (191U.
47 Gtuua. O.G.: Ntwttawtl, P.M.: Gawt>t. J, and Faua>+.w. L: Traroplantr,blc
malip?unt el+olsnsiwrcinoma from Aaertr li.er. Ardn snvir. HhA ?J: 137-1e1
(1971). '
41 Gat.Rt, K. and Jou.dow, N. W.: A quantuatirs uudr ot tAe inlla+ronuory raponsa
to elMmieally.indYOad aueinoma in AanrYr ohak ooucA. J. deet. RaL !i: 1062
(1974).
49 Gat.ea. J.A.; Caut+, G; MeGuw, t, aM Da Gua., T.K.: InAibitioo d
woeo~iedva! lamuv tye f autar wb aatiaaepw !wg unrn. troe. Am.
Atr. Canaer Rat. !3: 112 (197q.
30 Gaumurr. M. and Runwenua, K.: Comparathe rytopuhelo6ie aherationf
induced by alkylnittosatnina in ttua) eptAdieea of Nr iyrian laauwr.4. a.w.
Canaer Inst. !1: 421.J» (196f).
31 GRtxtwx. tl. N.;11rns. J.1., and OTotxs, W.F.: Role oltsrriv psrticles in Utio
induetioa of broncftial tsnar in tumtu.n by poiaeiwtr316 alpl+s rsdi.t;oa. Radu:.
RaL a: 2s3-23t (1971).
32 Gvnun. J. and GwrntR O.A.: Embrronal areineet» in Srriaa kanrtsn sner
intrat.uicvlar inoculation of pno d+loride dtrinS teaaaeial twitwar Srw+k Conoer
Re-t. JI: 2612-2614 (1974),
53 H.s. H.; Mot+a, U, sed KaUua, F. W.: Caeparatiw tuodin .itA difaeat doses
ef N-niuawmorpAoliex, tu+d diartAYleiuaraatisa in Syrian
golden hamsaxs. !. eate. l:anar Inu. Jl: /293-t301 (1973).
34 H+wnto.r. J. M.: Fuss. A: Su w., F.G, and M.ouuu;, S.: Honntu+ally inductid
rowl neop4.ia in the male Syrian Aanyter and tAe inhibitory diert of 2brano-
arpoayptine ntetlunaullonatt. J. nau. Canav tnft 31: i311S-ia00 (1f73)
33 HAua. G; K.ur.ua D.; boau+. H.; frour. M. a.d S.nqtr4 U.: Morpho
ruwit ot aquunous dl areiaonu and ioeallstioa af araPASent ia the trsprtr
tory eaitAdiwn ef tAe luaxur. Fed. Proc. Fed. Am. Saa up. Riol. J2: tq.S (197)1.
36 H.afs. C.C.; KAVr+uM, D.G.; J.cs>r>K F.; frrrw. J.M.; Dca+ct, t., and
S+»toTtb U.: Atypieal ellia in the traNeobrondtial epithelium ef ttr lamua dv
bi respiratory arnno{e+tn[a. J. Path. t1aeL I1I: 17-1f (1975).
$7 H.aut, CC; K.unur+, D.; Sroaw. M.; Roat>r. H.; Jasaoa4 F.t Srnx. 1.:
Fansr. J.; Duuesc. t. and S..nvrn. U.: Csnea RaL JJ: 21N2-2141(1973).
Sa< H.aaa. CC.; K.u.w.w D.; Seoax, M., ud SunoM U.: Histogensit of +qwa
~
~~~ '"'
~
~~~N 0~~ =
t
' =1
Cbanieal CareinoScnesis in Srrian Hanwen 171
ewas etU esreinonu of the respiratory tpMeliwn Is an aa7mal model. Canoer
Chemother. Rep. (Part 3) 4: t3-S1(1973).
39 H...is, C.C.; KAUrrA>r. D.C.; Sroaw. M.D.; Swrt'w, J.M.; l.ccsor, F., and
SArnorn, U.: Ultrastructural effeeu of N-methll.N.nitrosoura on the traeheo-
bronehul ephhehum of the Syrian dolden banuter. lot. J.Gnev 12: 2l9-2H (1973ti
60 H.aais, CC.; SarumuV, T.; S.mM, 1.M.; J.ccaow, F, and loRaw, H.O.: Fra
lifention of tneheal epithelial allt Is normal and .iumin AdeBeieat Syrian Soldn
iamuers. J. naun. Canoer InaL JI: 1039-1062 (1973).
il Hnaan, C.C.; Sro.rti M.>l.; Katnwrr, D.C.; S.ant, J.M.; 1.ctnt, M.L, atd
S.rnarn, U.: M+te ul(rastruaural e8eeys of banse(a)pyrsne and ferrb oaide on
the hamster traeheobronehial epitheliuta. Canar Res.Jl: 1977-19p (191M
62 Hruaa, CC; SroaM, M.J).; KAtmurr, D.G.; Srrrt6 J.M.; J.atinw, Rb, aed
SAnarn, U.: Histop+tesit of aqwmxxat metatdash in the haatstar trneheal ap
thelium caused by riumin A de/lciency or bamo(a)pytene-ferrie oaidt. J. rtt.
Canoer Inst. If: 743-761 (1972).
63 Hnnr, M.C and Kanw.n, D.C.: Clarnnae of lenzo(a)pyrene from Irssw
Iunp after ada.in'santion on to.tad panicks. 1. natn. Canea Inst. Jl: 1961-19N
(1973).
64 Hwnr, M.C; Fottr, CD.; S.ftt, R.R., and KAUr+s.rt, D.G.: Rap'vatery ena
tumors in harmurs induo.d b; benso(a)pyrene. Canar Ret JJ: 1SIS-1592 (1973).
63 HtMar, M.C; roaT, CD., and KAtmr.N, D.G.: leqortaea of Ohysial orop.r.
tla of bauo(a)pyrsrr-ferrie o:ide mistura in lung tumor inductiod Canaar Ra. JJ:
207-217(1973).
66 Hua", K. MCD.: Adenoaralnanu of the ietaty+e Induced in Syrian Aaewn
by N-enethyl-N-nitrorourea. hthalL vet. d: a03.412 (1969).
67 Husow, K. MCD.: Allatoun induced iaiorn i. Syr'tan 4n+nerts. !r. J. Curoa 2J:
6Si-" (1969).
68 Hteta, 1.C; Htan, M.; Wws, G. wsd ?laztn+, G.=.: Se6/waw Aa+wuaM.w
and b4dder anen. hnaitoloSy 69: viii-it (1971).
69 HtLrstcw J.; l.uu, J.; Ar.r, L wtd MoNa, U.: Msthodisdt einheh. Criodir
ptottit aneiewpel~otdursie+ter LunSen-Terronn am tyrsehen Goldhanwat. L
I: re4sfoncft. 79: 71-71(1977).
70 Hnrurcx, J.; latacn, H.; Marap,l, and Maa. U.:1..utiptien oa tlsa araieo
Satic burden by a'v pollution in nxa. V. Tunron of the nspiratory uact in Syrian
dotden banwsn after inrransdwl YnsttWtioe ef bermo(a)oyrene. Zentbi. lkt.
ParasitKde., t. Abt., Osq. ! IJf: l9-61 (1973).
71 Wawx4 S.: Cardnopenie M.es of N-N'dfmahylnara.ovas on S7rias Irn+ssers.
Gann 62: 321-313 (19711.
72 Huuu. S.: N,N'-DimethyM;troaoun.-indu<.d tumors is raiat and Syrian Ituaaert
Aeu nied., Oluyama 2J: 333-331 (1974).
easie
73 Huowo, I.; H.rswt. K.; MaU }i. aed MrwA. T.: Ct+roitwpnie eR.cv of c
in Syrian aoldee hanwsn a.d the transptantability of induo.d wnwrs. Canoer Ras.
1/: 213-2i7 (1971).
74 Hou.vaeta, F.: The Syrian golden hamster in dtemial areinopnais ratrareh;
in Hoaau.uu Progress in experSmeaul tumor reaesrs4 ro1.10, ".16.t-237 (Karper,
Dasel 1961).
S..r i R 1 1 N S..rr 4273...}
I-
Howevacite
172
73 Howw.cta, F.: Chemical arcinnowt+ssis ia the Syrian Soldea Irnrtr. Caneer Jl:
313-371(1969).
76 Howauttcu, F.: Machanio) irritatim polycyclic Aydnor0oro. and snuff. Anths
Path. 9/: 411-417 (1971).
77 Howau.ou. F.: Chemieal ontinoCeePOIla in iyr(an M.ewa><; in Hor.u.en
Pathology of the Syrian Aantow. Aro{, atp. Tunotu Rat, vo(. 16, pp. 1l2-17S
(KuSar,lau) 19721-
7t Howu.ca, F.; H..vca, A.H.: Snso. E.: Hww. 1.-S.t VAw Dm.ca+. C.G,
and Rwnnt.0, A.R.: Adtmoaneinoma ef tht {landrlar stomach follo+in6 3.
me:thykholanthr9ns, N-nitrawdieth)lami+., a Naiuaadimeth)tamine feodin6 in
nroino6en..uaaptiels inbred Srrian Lanwsrs. J. uwta Caneet itut. 37. 1t1-1a4
(1976).
79 Howau.uu. F.i Hstw+t, S.tiS.; Ktiatt. C.f., and Rwntta, A.L: /nht,riud sus.
teptitrility of inbred tutaim of Syr'saa Aateues to isductiea of wbcvuraouw iu
eeenat and mammary and purointatinil careinomai by wbnuaneau and pstrie
administruion of potynuclnr hydroorhont. Caaa+ Ros. JJ: 560-166 (1972).
10 Hoa+nuacia. F.; Htavat, S..S.; RuwsiO, A. L; LAlno. C W. and oAM DOwcw,
C.G.: Ab.ena of oronosenie aReets of ehronio fe.dhtS of wwQ in inbred Syrian
hannttrs. Toxie:. apol. Pharmac. Ji: !SS-f21 (19T6).
ti Horau.ea, F.; V.w De>,toot, K.; H.sot.al. A, and foto, !: `Naohulylanlin..
(ndueed urinary Wadder eanoec M(.bed tpei.a R101r.wrn. Abu. !!th Arow.
Mets. Soc. Ttuiedopr, P. 171 (1976).
82 HO.M. Y.; Lsw. i. S, and locuaec. A.: Sirort and leeyttw n naooet,a ot DM tA-
induead hatrotar chaet poueY weieoma to ahigh daa of rndittioa. J. thaL Ra. Jtl:
1352 (Int). -
WIro, N.; M.r..aao, K.; Atut, M.; YoaaOa.. Y.; Ka+.rOto, Y.; M.itnrtu4 =..,
tutd Suetwu&, S,: FJfin d raeious faetan es i.dret,bn of Irwry Maddv wntees
in animals by N-butY(N{4.hydroqbutyp niaanatina. Gann 6I: 1i1-119 (1977).
$4 Kavrw.w. D.C.; $Attsa, M.i.; S.attt. J.M.; Hoa~otot~ W.R.; Hiaae. C.C;
~ StwRM, M.L, and Sa+notTM U.: RNA mtxatwlisun in tradtsa) epthdiuni: Altera-
tion in hanntsn delit:ialt in r(tatNs A. ittit:noe Jn: 110f-1101(N72).
1s K.uea.rr, D.G.; GortA. V.M., an/ H.attr. C.G: fwdiw ea eeeine6en binding
96 in .ilro in uo(alsd hamaa tnetrrs; in KMatt aed Nuue l:PaaereW lun6 anoet:
Cuanovenah and Oioawyt, pp. i64-371(Sptilyar, la(is t971).
K.unt..4, D.C.; Gt+rtA. V.M.; H.1an, CC.; f.mrt. J.M.; SroaH, M.D., and
17 S.mnrn. U.: JlindinS of'Hh0ehtl benaa(a)pyrrtr to DNA ie Mmttet ou:Aesl
eplhdial alb. C+naer Ra. JJ: 2t77-2fd1 (1977).
Kimott/ctc. J.: Nt-rrsslt[Ir. I. and H.rwtos. S.: Twrner iadunia+ in tracheal
Srafu: A mw aaoerinrnul modd for rttapirstery otlRino6mafk tuudias. J. attt_
Canar leut.lJ: 1717-1)2S (1971).
q Ktrrrwr. A.R. and Lmu, J.a: Aytarad'apat>M' mint dry O+olwlt.d freem-dried
.euions for locslirsuon of araieo0eni ie IAa lun6. J. Hstedte+v Cyloc>+enL 22:
361-367 (1971).
a9 KIMe. R.J.R.: Swriw, J.A., and StieoU& A.W.: Owtroea.bindin6 and the ha-
mone respor<sisnoa< of tun+oun. Steroidologia /: 77-aa (t970).
90 Kucr.M, H.: Autonoeww dcrivatis of eao~eeieduaad raea) arcin~ &M
CTR. HN 0412""1"36
1
Chemial CantinoreKSis in Syriaa Hamuas 173
spoeuneow renal tumoea In the Syrian kaaula. Canar Res. JI: 272i-27M
(1974).
91 KtaarAw, H. and BACO4, R.L: Renat adenomas and aceinomn in diethybtil.
bestrol treated mak golden hanutvs. Anat. Rae. 10J: 475-476 (19a9).
92 KoMAr"n, N.: hoduenion of rsspihauory tract tumors in hamsters by benm(a)py-
nne. Gann 66: ]11-)13 (1973).
93 Koa+tvAf+u. N.; Horrw4^ D., and Wrrtont, L: A study of tob.aeo ardnepsAds.
XII. Erathelial ehan{a ieduad in the uppa ntpiruory anv e( Syriae Boldr
hamsters by eiptette smoke. J. natn. Canar Inu.lJ: I0ti3-1019 (1974).
94 Kouv.wt, N. and Or..roto. T.: EJteets of kad oa,de en the i.ductia d Ntati
lumors in Syrian hamsnri. J. eatn. Cancer lesL JJ: 1603-1610 (1974).
95 KowAuwsct. K. and Tooo. LF.: Careinoma of the pllbladOv induad In Ytttw
sters by insertion of cholesterol oetku and f.odinb dimethylnhraamins. rroo. Soo.
taO. Biol. Mad. IJd: 4t2-1i6 (1971).
96 Kuscwmca. M.: The auses of lung anar. The J. lums Aa+barson Ltetws. Aat.
Rev. rap. Dis. 9J: 377-390 (19d1).
97 Kwnuua. hl.; Watw, S.; Detw, R.T.; Carntu.0. V., and Ncuow, N.: lei.latioa
tarcinobenicity of alpha halo tuhets. 11(. Lifetime and limited paiod inhalsties
studies %rith bis(chloromahylJetttK at 0.1 ppm. Atefu envv. Hlth Jn: 73-77 (N73).
91 LAcwra., T. and G.a.ut64.. M.: B+oelKmial studies o( duthyluilbestreisduoad
kidney tumors in the doldea Syrian hanxur. Cancer Ra. !): 1231-123i (1971).
99 L.afow, V.M.; CLJRK, W.R., and HuUwaw, M.R.: Coenparative studie of SVO
and ada+oviru oneoBenais in nndoie brad and inbred hamsters. 14oa Sot aa.
Biol. Med. I)f: 607-613 (1971).
100 L.ua. S.; Dncw, R.T.; Gmtu.o0. V.; KUewrwM, M. anJ Natapw N.: Inlml6-
tion arcinogcnanty of alpha bslo eeMn.11. Chronic inhatauot uudie.ith ehfoes
axthyl methyl ether. Archa envir. }ptL Jo: 70-72 (1974
101 Lsu, K.Y.; Tont, B., and Stlwt, P.: t]reinopsie nspoas of the Slni.a Boldea
hanuier treaud at bmh with 7,12dimdhylbwlapnthrawnc. hot Sae sa0. 11i01.
Med. I II: 579-512 (196)).
102 Lrran,awu. R.J.; Lt. J.J.; Ro>a, S, and Vn.us, GA.: Junrtionat sp.ei.li:uioe
in avogen.imluced renal adenoareinomss ef the tlokka hamstv. Caam Ra. JJ:
6-1 0 (1973).
103 Lttvu. l.S.; Du><sr. A. and lbatues. M.L: The ef[.et ef ewrstiow on eienionl
arono'ennis ie the Chak pouch of the Syrian golden AsmWer. OrMI SurS. Tl:
709-712 (1964).
104 Law. l.S. and lasuesc, A.: Lyinvown va-6ka Aanrter d+.et pouch with tooiol
vitamin A almitsta. hthol. Mietobiol. JI: 2i2-2f1(11M).
103 Law. L S. and Pauat'e. A.: The eRea of nea+bnnaee+i.e aPmw ea the etitoaie fray ouency in normal
and arcHOda~u.aud epitbliws E+aern.ar lI: MJ-ii4 (1972).
106 Lrvu, I.S.; RworuaMAxa, J. W,aad Pa.Luws, I!~: Erten ef wqieal cydophasph..
mide. methouesaer and vinblastine on 9,I0dimethyLS.2.btwanthrsosn. (DMBA)
areieo0enaet in the hantsta eh.ek pouch. Eur. J.Gneer 6: /It1-19J (1970).
107 Lt, J.J.; TAaur. D.J.; Lt, S.A, and Vtut+R C.A.: R.cevtoa efunuuripia of
spciRe etrojen bindind in the renal adtaocareinoma of tM 6oWen hanuter. Cancer
Ra. Jd: 1 t 27-11) 2(1976).
C" T R 11 N 0 4 '227,23 '?
/1
Howauacta 174
101 Ltrn .1.B.; GaossMAw. B.N.; MCGAA9Y. R.B.. and OTesat. W.F.: lnflucnoe or
geneiic strain on tAe induction of lung eantsr in hanrters by aipAa tadiation. Ew.
J. Caneer 9: 123-121(197)).
109 Lrn.r.1.B.; GaoesmAN. B.N., and OToots. W.F.: Induet)on of eroncl~ial onesr
in Nun»ters by potonium-210 alpAa radiation. Radiat Ra. fJ: 2fI-262 (1970).
110 Lrrru.l.B. and OToou, W.F.: Respiratery traet tun+ers in Inntaten induced by
lenm(a)pyrene and "Po o-radiation. Cancer Res. JI: 302b-7019 (1971).
III
112 l.t.outAaTBatw. A. and 9tru.o. A.: MarpheloBial. Aistoehanieal and uhn-
struaurai oDserYations of diethyluilbestrol.indueod Yidney"wmas in tAe Syrwn
golden lunuter. Eur. J. Gnoa ll: 403-412 (197i).
A1ACDo.At,D. D.G.: EYSluation of EpitAe)ial atypia scoring in eaperimental and
113 Aunun oral prernalipnney. J. dent. Res.l1: 923 (1973).
MAtswaMA, N(. and Susuer. H.: Adrpnl wmoun and endocrine (eeiqm induced in
i Syrian Aanxten by trretAarK injeaed darie/ sucklinp period. Br. J. Cancer 24:
712-11/(1f"1.
114 MAtsvYAr.. M. and Svtua. H.: Induction of eaumreorna by injections or N.
I
113 nit roiobut) lures in sw 11inp 5yriun Solden Aanuten. Eapt:riesu ia 17:1139-1160(1971).
Mct.wtn.m. A.9. III; K><ssus+, W.O. and Gmss. R.F.: The dissociation be.
t"en sndaeYVU s.etieoVrrs's and annee tetiBtaieity. I+tpeatre Urol /J: {1-57
(1974).
116 Mtltu>ti M.: Me4loBt tetivatios of 4WAybdIbeaval: lydir.et eYidenoe for the
I formation eh urea. a.ide +stanrdist6 in haart:r and rat. Biod+ent. fbarntac.2l:
1449-1413 (1973).
117 MoMa. U. and ALnon. J.: Grdnopnie aetiYitr of tlipAatie nitroaantines via the
maher's nult in t!r .Rsp'stB of Syrian Bddan Rarrwaas. trot. SoeL asF. Eiol. Med.
IJ6: 1G07-1001( a 17t).
111t Mowa. U.; Ar.rwar.l.; E+ttins;,a, A.; hltlen. H. and Snatssolr, ll.: Elfect of
i aiuosantiew on rr.iau Srrita Bo(tMn \uruteaa tad tAde oQsyriay. 2:14sfystoneA.
78: 73-77 (1972).
119 MoMnsa+q R.: Sywe-+ie tareinolem (N4trote tanpounds) and pnsr/isuc or
~ additive eReeu in nsplratery nrcisoBetria. Twnati 59: 233.1e4 (/f70).
)20 MomtaArro, R. end S.rnarn. U.: Carcinopenie napomi of Ne rspiratory traa or
i
Syrian lolden Aanrten to diRermt dats of d+abylaiuoeamir. Caatiar Res. Jf:
2197-2210(1981).
121 Mowmaawo, R.; SArnont U.; Ftotatato, A. and. Kaursuw. D.G.: Synatistic
I
22 eRuea of bauo(a)p7rene ard diedtylnitraambn oe repiratory eardnopansa in
Aanxten. J. natn. Gnaer Inu. JJ: 1)9S-12t7 (197a).
P.: TM roM of topica) and sysunne
Moo%"rstaro. R.; S+nrorn, U
and Swunt
1
I .
.
factors in eav+wrmnNl restwratory oronopenais; in HAwwA. NsTnsa,uw and
Gtuut IMubtkm earsr.open.w. AEC Sytnpoe6sm Saia No. I I(CONF491001).
pp. )33-3M, (1 "01.
12J M uatxY. A. S. K. ed Ranyta. A. B.: Dehydro{erusa in diaAybu70auol.induood
124 kidney tumon af tae Srrian Mnnter. Esperientia JI: t10-~I (19d1)
NAGASAx4 H.; KAw.1ArA. H.; MrYArA. Y.; Iwovt. K.: Huto. K.; Aa. H, and
i ho. N.: ERat d Yanwu faaon on iaduction of li.a twnors im an,mals by the
aipha-Wrrtr of 1 xar Aesacisloride. Gaan fi: II13-191(1973).
Lr f i"r f 13 7 0".i. 2-738
d h
Chemial Careinogeneiis in Syrian Hannun 17!
123 Nerrwntw, P.; Car.a., D.A., and Mtrctau, T.J.: CardnoSsnie and coaecima
Wic eReets of inhaled synthetie sntot and farrie oaide ponieies. J. natn. Cancic
Inu. J!: 159-169 (1975).
1:6 Or.sv, R.; Krr.nw., T.; Hon, M.L, and Susnt:, H.: Enhaneemenl ef tvinary
bladder tumorieenais in hennten by eoadministnuon of 2acrtylaminonuoeute and
indok. Canctr Res. JJ: 2027-2033 (1972).
127 OrASv, R.; Ktiwnro, T.; Hon, M.L, and Sunu, H.: Induenioa of Wadder oanosr
in sawnsrs by sspsatod inustraclral admin'suuions of 2aoesylaetieoAuos.nt.
J. natn. CGnox Inst. J0: l03-i06 (1973).
128 Orsu. R.; Suwu, H.. and Btmo. H. E: Neaplasnr of urinary bladders of tunrws
treated ..;th 2-aonylasninoAuorene and indok. J. nasn. Canar Inu. IJ: SS3-160
(1970).
129 tKrsa, M.S.; Sw.:aort, D.H., and Coenw, D.L: 6lfest of oa,one on berttpyretr
hyJroaylasu activity in the Syrian golden hannut. Cancer Res. Jl: 730-713 (1971).
130 MwaCC, A.: Shon and lonpurm responses of OMBA-inJuoed hanrse;' ebaek
ooueA arrinorna to a hiSh doye of radiation. J. dent. Res J0: 1732 (1971).
131 rou.uet, A.; Ctuuu:r,1., and Law, I.S.: The etfect of testoaerone on eltentieal
eamnolenau in the bueeal oouches of awrated and intaet male h.nrtessm htAol.
Miaobiol. JJ: Stl;-336 (1970J6
132 tous.CC, A. and ltw,1.S.: Ieereaaed inodems of sardaonua induced by DM1>A
ln the 4nuter cheek poueh in raponse to viumia A. Nawne, l.ond. J/6: 1t7-lii
(1967).
13) rousa.M A. and Law. I.S.: The elraa of sopiwl Htamia A on p.piUonrs and
intracpthelial artinomts indutxd in hanuur drek pouches with 9.I0-dimethyl-L2
benranthraorne. Cancer Res. J9: )27--0)2 (1969).
131 hxu.et, A. and Lsvv, I.S.: Astineop4seie elfeet of ehlorvrenrtier ie drmical
wednowercsis in the hanrur d+.ek ooucf. Canor Res. JJ: 1912-1915 (t972).
133 touL.ct, A.;11w,1.S, and Rwont,wwa.1. W.: 9,10Dinrthyhl,2benastM
e¢ne arcino{erstsis in the b.err eb.rt pourh. Archs Path. 00: 19id9t (I970).
136 Porocv. N.C. and Csot.ot'A. L: Chromoeeer of dirnieally induos0 tunrotts
after twrsour polypassaBe. A4epiaant, /f: 1S-I1(19711.
137 Poar,C.D.:Hurar,M.C.;K.ursun,D.C.;F(.aae,C.C.andKmsa,K.V.:Aest
ehanaa is Ihe surfaa morOholop ef hanrav ttaeMWroncaal etHthelium foUo.eeeS
bceto(a)pyrsne and ferrie aaide adnsininratioa. Cancer Res.JJ: 2e911-2506(1973).
131 Ibswtuo, D. E and Cowerr, R,: Inhfbisien ofeseeiaoBeassis by dieury zinc. Nawrr,
l.ond.JJf: M7-4/t (1971).
139 PorR. F.; Torn+os. R, and Ravrat, F.J.: Estesis w ul studio of the tarcisso-
Benieity and the raentioa of beaso(a)pyeeae in applieatioa reban afur insratradwl
and subcutaacotss injection. ZnubL ItaILt. hrashKde, l. Abt Orig. D/Sf: 97-108
(1973).
140 Pova, P.; Gaoan, A.; Aussoet, l., and Mowt, U.: Tumoripne's in the awnl
olfaetory refion of Syrian tiolden hamsters as a nsult of dw.propylnitronmine.
Carm Ras. l!: 16-21(1911).
141 Pout, Is.; Kwoett, N.; Gausest, E; Mosn, U.; Atrwn, J. and C.awa.. A.:
Spontaneous tumors and oonunon Jbeasea in two oolonin of Syrian hanrten.
1. Incidcncs and s+ia.1. navt. Cancer Inst.36: 931-933 (1976).
t..r Tf b f f i i 04 2`73...+
How@unGta
176
142 Poua. P.: Ka(icsa, F. W.; At.rrorr. 1.; Gaow, A., and Mowa, U.: ERect of.
d-o:idind nitrosamines on Syrian golden hamsters. 1. 2.Hydroaypropyl-n-propyl.
ninnnsmine. J. natn. Cancer Inst. 52: 1213-1219 (1974). 143 Poua, P.: Ka(kora. F. W.; At,nton, J.:
CaorsA. A- and Mnut. U.: ERea of
aoaiditeJ nitrosamines oc. Syi n hamsters. Ill. 2.2'Vihydro.y-Ji-n-propylnitro-
samine. J. n.tn. Cancer Inst. JI111-Id6 (1973).
144 Poua, P.; KnOaa. 1-.W.; Aifworr. J.; Gaotss, A. andMan, U.: A new
approach for induction of ponaatio nee+plasrtu. C1MSr Res. JJ: 2239-2261i (1973).
143 Poua. P.: Kafictca, F. W.: G.ot:u. A.; M.taorr, J, and Mowa. U.: Carcinogenic
effect of di-n-MoPylnitrosamine in Syrian golden hamuers. J. natn. Canar Inst. Jl:
1019-1027 (1973).
146 Peua, P.; KaOCta. F. W.: Gaww A.: At.nron,1. and Mowa, U.: Tumorigenicity
of mnhyl.n.propylnitroaamine ia Syrian golden hamtten. J. natn. Cancer Inst. 52:
437-462 (1974).
147 Pot:a, P.; Katiara, F. W.: Ainan, J.; CAtoaa. A., and Mota, U.: Cancer of the
panertss induced in the Syrian golden hamsur. Am. 1. Psth. 76: )49-77t (1974).
148 Poua. P.; Moata, U.; Cnaows+ti A.; ALtiron. 1. and K.wnt. N.: Sponuneow
tumors and common diseases in t.o eoloeies of Synan hamsters.ll. Rapirautry tract
and di{uti.e system. J. eatn. Cancer Inst. Jd: 937.ft1(1976).
149 Pourt. P.; Mort.. U.; ALnan, J.; C.aoa., A., and KMOCw, N.: Spontaneaa
tamors and aemmon dilamisw ie t.e eoionio of Syrian hanstere. 111. UroSenital
system and endocrine glands. J. aatn. Cancer Inst. Jd: 9/9-961 (1976).
130 Pntv. LN.; Rtx, F., and Vo.vra, K.: A studv of the pulmonary tisrw of hamsters
In raponsa to the intntneheal insuALtion of tritium labelled ('H)bens(a)pyra»
miud .-th artwn trlset and asbeuas. Pa;oi. Fi:iol» MoKo.I:17-l1 (f970).
131 R.r.outti J.: A ner appro.ch to the use of the hamster drek pouch in tatinS
eareinotsanic subuant:ta requirin{ sspeated replaoenrsu. lsdian J. Canar Il:
404-43 (1974).
132 RuNttc-ScwUtua. H. and Mowa. U.: Inveuiptions on the nreinoSenic burden by
air pollution in man. IX. Early pathotogical alterations of the bronchial epithelium
in Syrian golden hamsters after iatrstrae:hal instillation of benra(alpyrene. I. Mor-
phdo6ieal tuudies from sanitAin sactiont. 2:.ntEl. Lkt. ParuitKde, 1. Abt., Ong.
2 159. 493-302 (1974).
133 Rrtwhr.SmtOuu, H. and Mam. U.: ImKstiptions on the nrcinoSenic burden
by air pollution in man. X. Nsorphoiogipl chanpes of the aracheal epithelium in
Syrian golden hamsten during the Arst 20 sels of bento(a)pyrene instillauion: An
ultrutructur.l study. 2sntel. Illakt. PanaitKde, 1. Apt., Orig. 1 lJp: 30J-323
(1974).
154 RarmcStitOtji, H. and Morra, U.: In.ntiptipu on the areirro{enie burden
by tir pollution in man. X1I. Early pathological alterations of the bronchial epi-
thelium in Syrian Soldee hamsters after inantracfical instillation o(ks>uo(a)pyrens.
2:enttsl. Lskt. PansftKde, 1. Abt, Orig. b/60: 10i-129 (1973).
133 Rv.MC-SntUurjt. H.; Rezrax, G.. and Moeie. U.: Effects of e+pretu smoke on
the bronchial epithelium of Syrian hartrten: Ultrastrucnural studies.l. natn. C.a nov
Inst. JJ: 333-JN (1973).
136 Rouat, A. E.; Awanrow. H.; Lu+w.wr. G. M.; Wou, G, and Nt<wearrt, P. M.:
t.x t R f i i j 0-'T' 27"'i' 0
Chcmlai Carcinopenait in Syrian Hamttera (77
A temitynthetie diet for long-term nrintenance of hamtunt to uudy.Rceta of dia-
tary vitamin A. Lab. Anim. Sd.ll: 4934" (197p.
1S7 Ruat., D. and Ltw, L$.: Suppression by vitamint D, and D, of hamttsr dwk
' pouch earcinonu induced with 9,10-dimethyMl,2-benranthtaoms. Patho). Miaobol.
!9: 116-460 (1973).
158 S.rnorTt, U.: Morphologyof respiratory tumort induced in Syrian golden haatctat;
in Ntrrswna, H.wwA and DturwtaaGt Morphology of capainrntal repratory
ardnopenait. AEC Symposium Staia No.21(CONF-700J01), pp.21S-2f1,(1970X
~ 1!9 S.natrt, U.; Cvn, F.; Mowm.wq R and Stuuw.R, A.R: lndtstien of
bladder pnar in hanutert ftd aromatic atninq; in Lwn lladder anar, pp.129-
13! (Aeseulapiw Pnet, lirtniniltun, A1a 1967).
160 S.morn, U.; Mor.ro.w, R., Sty..~utr.a, !.. P. and baS, S.A.: Etoaamnt«
anar of the lung: Inhibition by vitantin A of the induction of tnehoolsroeehial
.pwmow metaplatia and tawmote cull tumon. Canar J0: t37-i61 (1967).
161 Sarnorn, U.; Mot+ro+tw, R.; Stt.tAsttt+aa, A. R.; Ctm F., and K.urr.w D.O.:
R
i
i
i
rotory traa aranopenab
ap
a hanKtcn
nduad sy diRtnent wenAcn of ad
-
ministntions of beatso(a)pyrant and itrrie ositk. Cancer Rea.l2: 1037-10t1(1972).
162 Scnu.ueta, F. A. and B.wwuet4 P.: Toaiefty and eattaropenie propeniet ef idvtled
dimethyl tulfata Arah. Phamukol ?66: NI (1960).
~
163 Saatiata, H.; M.amt, D.H., and Psr.nwo, N.: Species d'JJJaenms in tJr effect
of bento(a)pyrataferrk oaids oe the rapirftory trat:t of rau attd AanttMn. Canest
Res.1J: 161i-1661 (1975).
164 Smwaca, H. and Nrrrmuut, P.: A m. nxt)tod for pultttonary cytolow ia nu
and hanutvt. Cancer Rat.lJ: 737-743 (1972).
163 ScManata, H.; S.ceoa.rrw, G.; M.atm, D, and laauuw L: S.ounttial tyto:
logic changes during de.dopmt:nt of twpiHtory trttp tummt induwd in Autwert
by Eento(a)f+yrenaftaric ttaide. Csttar Roa.ll: 6"t (1974).
i 166 k-wauttu, H.; Sovutraa. K, ana Manta+, D.H.: EattaiarntaP tttt*ar indtetioe
!n a arcvntttsibed re6ion of thc 6ammer traosr: Correlation of hittoiop attd
esfoliunve cytology. J. ttun. Cancer Inu. JI: 6a6-Oi1 (197i).
167 Stuwctnua, A. R.; Moantaaoo, R.; Sanwtn, U, and K.unytv, D.O.: Hanctrr
rapvttory an:inopentsfa induad by bento(a)pynatttt utd diRasl dow lt.eM of
fcrric oaide. 1. uate. Canar Ittrt. 30: S07-S10 (1973).
! 164 Stu.Azuutt, A. and SNurtt, P.: Csrtanopsnieiry of 7Hdibat=o(eSlarbamM ie the
! reslMrttory trux of hannurt1l. >easm Canear Itta. q: 16/1-16u (Im6
; 169 Sun.izu. H. and Tont, 0.: Elfiu af lUaimc admi.ictrstion or 24ydroa)sthylhydn.
1 zint on tunrorivffmis in hanrters aad rttics,l. nam Cancer Intt.l2: 903-906 (1971).
170 SNtttaa, G.: The effect of tnanipulation and faeisiott on atperinrntal aronoatm of
lunuter Auoesl pouch. Cancer Rat.2l: 21W21t2 (19611.
171 Sltatt, W. V. knd SNRtaa, O.: Tir alfia ad dtmnhy/ wtaaade and topKal triam.
cinolone on elKm.wl amnopenesa of hamttat Mml pouelL Oral Suri. 27: Tt2-
779 (1969).
172 Swrtn. C.1.: Vtviatioat in histod+anial propenin of hydroytic attye+a in owt
pnaonarous conditions. Hcl.. odoet. Acta /J: 100 (1971).
, 173 Surnt, C.1.: Variations in histadkYnical propenia of hydrolytic sns)rsKt la oral
pntnnccrow laiona. 1. dent. Rts.3/: wppl.2. pp. 30t-71t (1972).
CTR HN 042 >r 41
\
HaMau.Ga
178
174 SwTw, D.M.: Rooeaf, A.E.; HcarrDONK tLl- and Newsriml, P.M.: Vitomin A
(retinyl aatate) and benro(a)pyrenainducM rspiratory traa tarcino=tewil in
hanuten feJ a eommersial diet. Cantw Res. JJ: 11-16 (1973).
173 Swmt, D.M.; Roaeas, A.E; NtwwRk4 RM. at'td \vuaor, R.S.: Vitamin A
and Sento(alvy ~ (BF)-inJuoed nspirataY twnaes+. Fad. Frx. Fad. Am. Soa ap.
D'a1.12: 9//(1972). '
176 So, AT. and Wnnxa, LL.: lnduction off hannta ttoetoe~ of the urinory pydder
by 3,2'dimethyl.&aminobiphenyl. l. natn. Guuv lraft. q: 17)3-1733 (1972).
177 Sresedctc, F.: Mo.pholoSie eharaeteriuies of aptximentally induted lung tumon
and their proeunan in hamstas. Aaa eytol./7: 476-4t6 (1973).
171 Stst+aictc. F.; Fra.eao0. A.; MowrwM0. R. and S+wattc. P.: Synergistic eRat of
ferrie oiide on dimnhylnUroamine areinopenew iA the Syrian Solden hamster.
2: Krel.forxh. 79: 31-311(1971).
179 STZrcaxec. F. and SeuAawAa, A.: Sqtsunetu meuplasia and raMratory wmon
induced hy intravaefinl instillatqru o(7,12.limethyfbatz(a)hantMaeene in S)Tian
`
polden hamaten. Eur. J. Cancer 10: 4q3-4t6 (1974).
lit) Snwatett. F. and Seu.utuwut, A.: Lung tumor induction by dibens(u,i)pyreee la
t)r Syrian polden hamster. Z. Knlefondt. 82: 173-1u (1974).
ISI Srmv.ar, H.L: Eiperia.atally, iinduced pstrio adweaepnontu. Maude Abbott
lxture, 1971.1Ab. Invssl.ll: 674-474 (1971).
182 Srtuts, W. ard Fnak. V.l.: Uhrastnrctur+ of puhnanary adaromas induced by
MtratreetAnl imtiltation af dboftlakrowmine in Sye'se poidae lueuteR. Eur. 1.
Cancer 9: 339-K2 (197)).
183 Twsc.. C.; HAAa, D. und Gouttnta, K.: Cytephotomariselr tdunde in der Tra-
trhnlschleimAaut und in DANA-OaAanddten Trachealpapillomm beim eyrnchen
Goldhanuter. t?uenutative Ustanue8unpee atr Eotdidertesieuas. Z Krsbeforaeh.
74: )33-767 (1970).
lH TotM, !.: Orarian and otMr twnor isdutxion by 7,1Z4iteateylsent(a)antbraane in
tAe Syrian hamster. Tumeei 17: 169-110 (1971).
183 Totti. 8.: Tumor induexion by IepateJ inpctione of ursthan in newborn and adult
hanuters: Age mnuence. J. rmte. Canoer lttst. N: t1-92 (Irl).
186 Totw A.: Tumorigenes's etudiat witA 1,2-dimethylhydrasine diltyJrochloride. hy
druine eulfate, and Iwniootlaio aeid ia polden hamuaf, t:aear ReL Jl: t0+-607
(1972).
187 Tont, !.: MoryAologiol ttudia of anCiourrornaa induced by 1,2dimnhylhydn
sine dihydrodtloride in Syrian golden hanuurs. Cancer Rett.J1: 2l111-2t27 (1972).
III To»t, B. and SMna:u. H.: M.thylhydrazine tunnorigenesh in Syrian aolden ham.
stas and tha arorplwlogy of malipum Aatiocytonn.. Canoer Ra 1J: 27"-27l2
(1973L
119 Toro, F.D.; Mu.e.u, H.; F.oL D, and Rurrarutt A.: Effect of human Wira
on eanoer iMutt.on tn hamuo pouch. J. dent. Res.3J: 364 (1971).
190 Taro, F. D. and Swanat, C.: Fremaliptant DNA eynthta's in tfaeroter pouch. Cral
Surg. Jd: )93-)96 (197)/.
191 VAM Hoosaa, G. L.,1r: SNCrr 1.G, and Tnt:wnM,1.J.: Compantiw evseeeutiility
of noninbed and ttrain LSH inbred Syrian )urvten to oncogenit adcnowus.s.
Proc. Soe. esp. ". Med. IJ4: 427-429 (1970).
C ~' ,: ~~~~ 0 ~'~';~~'~
Chmnieal CarcinoSenab in Syrian Hanuters 179
C
192 V.avaucS, M.1.; S.Mraow, D.; ScwooMa, R.; C.er., 1.F.; Rtrwomo O.;
Mta.wu. EA., anJ Muantv, C. F.: Tlr eRocn oPanJropu and esuepte e. indueM
Oroautic wmor in the hanatet. J. wrL Oneol. I: ti-S! (1472).
191 V.ptavA, N.N. and Miurvsr..vti I.L: Embryonol rh.tedomyee4stomn indupd
by methylnitrowuro in the ehaek pouch o( Syriau iianstas. Syull. eksp. RioL 72:
71-75 (1972).
194 Wta.uaosi., J.H.: Colan areino/ero; T1tar artababm sd eoda af aesie&
CaeKa /l: iO0 (1l71).
193 Weeau.aat, J.H.; Garuern.r., F.H_ aed Wawuso0. L1L: MwYo(ita. Kl4.y
(lYorenylaccumide in the hanteut. To:ie. avpl. Flnrnuc 1: 4M.4)2 (1f6q.
1% Wimm F.H. and SGUma. CA.: Aquaotitative atu4y or tAe eamsdlular and Onrl
tuthmau apparatw bt hanrl.r eAaek poueh eoithdiuttt dei.S eednopetsiL
1. Oent. Rx. JJ: 1072 (1l71).
1!f Wtncwt, H.: The eRecti of diMytninnmin. on eiloirn:Mic aW ad Oreale t+yt
tha'r in the liver and lunj of the Syrian Soldm lanwe. laehra 1. IJf: 7tf.7!4
(N77).
Ifi Woom D.A. and Srotu, G1.: lldrastruewn and Oesiotrn.ent of epithdial odl
Osudopod'u in cJwniealy Lnduad prstnaliymnt lesioes of t!r bmtar eheek oarcd
Fspl amoMam hth.11: 160474 (147i)).
!!! Wnmt><, E.L and Honr.rrw, D.: Tobaec+o ud tubaeo ano1L Studiu I@ e:ptri-
amual earcinoSeaesiti pp.11l, 242. 241(Aodnnit: Trs, Neo York 1fd7)r
(USA)
Dr. F. Hanvaoa, RioRecarch ltwitute,! Coevnaeial Avenu., t:..A..*e, MA011f1
~N ~~#~~~"~~~
CTR
;
T:.' r..iifr:a ir:y be
;r:tccbd by ccp;r;j1t
lew Rtlra 1Z _U.S,. Codeg
Progress in Experimental
Tumor Research
vol. 23
Serin Editor
F. Howitrno0. Csmbridr, Mass.
@F
S. Kucer Saul MGacben Paris Londoo New York Sydcery
CTR HN 042744
~I
Oncogenesis and
Natural Immunity in
Syrian Hamsters
Volume Ed;cor
1.1. Turmn, Houston, Te:.
l l djun. aad 32 ab1.,197f
S. Ktrjer Bud MGncben Paris Londoo New York Sydney
CTR MN 042745
Contents
C
S.rir EdltoP, Fonwad .............................................. DC
Volvra. Editor', Fors.w ............................................ JQ
Nanvally Octurbej Twnors ojdlt Syrimr Hanurei
0. L VAn Hoaas., jr. aod J. J. Taama, Swnk, WaAd . ................ 1
Ietrobuaioe ............................................................. 1
seaifn Neoplasrn ........................................................ 2
Malipunt N6o91tuK ..................................................... 4
DAeuuion ............................................................... t
ltsferencs ............................................................... f
Tmno..4uociatte Ylncm oJtAt Syrian Hamttn:
Rdalion to N.oolado
KJ. McCoamotac .ad JJ. ThanK Hounoa Ts .......................
13
Introduetloa ............................................................. 14
A{eea to ]k Cari0aal .................................................. I!
Hatmar haovsvirw ..................................................... IS
Dboor+rftud Oo:vr.oar ............................................ Is
Studia of V'ra! DNA ................................................ 16
Oetollmititr ........................................................ 16
llType hrtclt .... :..................................................... 17
Dhaoray t+ad 00.vrritea ............................................ 17
MorpAolm .nd Derelofmra ........................................ 17
Nuckic Acid ........................................................ 18
RNADspendeat DNA lolrmerau .................................... If
Adated hrticb fe otAa Spni. ................. ...................... 20
Isiolopol Aeaiviry ..........:......................................... 20
L. r f f"'.. _ {{ N 042746
/1
CADISM
tntraeytoplaaoie AType tartid. ..........................................
Dieevery and Oce+arrsnor ............................................
h.euesar of 11'. or CType V'rienf .....................................
Diodwnial Aur.etairaLion ..................... .................
C-Type Vhuf ............................................................
....... ..............
D{uor.ry ..................................
Oavmaia.ad Anadodee witA D'eme ............... . ' ................
Clwsnvi"Lfoe ef Nonief.aioua HMu.r GT7ae Vkioe. D! .............
s0101W .........................................................
r«h.lniffil ........................ . . . . . . . . . . . . . . . . . . . . . . . . .......
lnrnvnoiosinl..................... . . . . . . . .. . . . . . . . . . . . .... .......
Viruwt Auoeiu.d viia Hanw.r Twmoes isd,iad by Mrria GTpqa V'ww
The Vinrs ... ...........................................
Anu{enie Charaaaizalioe ..........................................
EiOdism" Chullclxiati00 ........................................
Aetivltion of TametAtwbaad Virws .....................................
}iannter laooq.inr ..................................................
Th. RTyve hnisl. .................................................
lneraeyeoptaunie ATTOo ianid. ......................................
C-Type V'vioe ......................................................
ttwnn ef Type C Vird Astiwe lo Hama.r T.eeon ...................
tpomaamr Aetiwties ............................................
AaYv.tion bf a DNA Vkw .........................................
Activ.tion by Onoeen.rirur .......................................
Iemmwwlopd Aairuios ..........................................
Mi.odliewar ...................................................... :....
Commmtt ...............................................................
Aeknowk+dOnma ........................................................
RtfinM ...............................................................
VI
Umww/ Fednvet of tJu ORColalcby of Meka E+nbrye 1.efAd
OrDMn (CELO) Yirw Lq XmrWert .
EJ. Asat. KJ. McO*aaac sed )J. Tuxm Harto4 T.z ............. 56
Ineroduetion ............................................................. !1
Oeoo9enieitr ef CELO V'w ............................................... 3/
!. .M .............................................................. Si
h Wn,. ............................................................. u'
CfLO Vku.-Sv@We. TrswA.ociard Aatfpft ............................ !9
39
T Aetip ...........................................................
TwearSp.cifle Tnesptanratioe AwiOn ................................ 62
ltweus of CELO Virw Uan N.oplutie CNb ..................... .......... . 63
Oneolenieicy of tt.av. Varirona of CELO Vinr ................... ........ ... U
Aoie of CELO Vinr m Ir.oplaaic Tcuulordtia. ............................ it
C "°R ~N #~~~ ~`4"7
/1
cot+unu Vu
lropatief aCdl Lies FsublkMd /ran Tumon Iadumd by CBLO Vina ... 64
Dviv.doe ol GIlLinw ............................................ i4
C81A VUuw-Sv.eilk T AztiM ...................................... q
CELO Vitut Tumor.9paifie TnarP4eutioe Astiop .................. 71
Attat>ou to lt.cw CbLO Vinu lrae M. Tumot W/ Lia.. ............ 72
FroduKtioe a VLt by CELO Vins Twtror Cs!! Lbw ........... ...... 73
Quastiutin 1Wayt lar U.iur. TaeJonauioe by C9dA Vlnr ................ 71
Is Maeol.nr 41tur. ............................................. 74
le Soft Apr CLltuns .............................................. 7!
V(rvSp.e;no M.rk.n aea VLt `dM Tnedaeed 1..., by CELO Vin. 77
GUs Traettor>na i. Moso4y.r GL4uns ............................ Tf
CdL Traatforsrd b ioA Apr ..................................... 79
Comteenu aad CoeduYOOr ............................................... 79
Refuuwt ............................................................... M
Radiatiar Coreinotaettit /ot tAs Syrlm HmRtta
W.A. Ss>r.m M.E hrANaa JJ. Tsn+row, NousoR Ts .............
89
Ietroduetioe ............................................................. n
Itevinrof Rwmt Tapers .................................................. 90
a rim tmai.tioa .................................................... 90
!a .isro Irrsdialoe a Hamst.r Csl4 .................................... 91
Laducsion a NeopWms by WSolalody Rtpa.vn to XIs.dirtiaa .n4 Obeeva
tioro oe'Actir.tion' a Fb0o0eeou Vlnra .............................
97
IAtroductioa ........................................................ 9)
EtpWHf8li) rY0i14we .............................................. 93
Raulu sed Dsvr.iea ............................ .................. 9S
RslaIees .................................. ......................... !7
CAetelcd CanLtot.eatt Lt Syr(an HmRrten: A J4.hr (tArousA 1976)
F. lior.uwta, CamOcidOt, Mum ..................................... 100
Llacoduetloo ...... ............................................... 101
11.Skie ...............:................................................ 10)
1II.SuEeoun.otu Tirw ................................................. 104
IV.Cbwk toiicY ........................................................ 106
A. Malwd.......................................................... 107
R. H'siodarnos+y. Fies Struqvra. Cytolopr ............................. 110
G ModityinS Faeton ................................................. III
V.OsI Cariuy ......................................................... 11t
V1.ToeN. ..................................................... ....... llt
VII.ReDinton'Tract .................................................... 111
TrscNcal 1nuiJLtioo of Careiso0eeie Aps1t ............................. 123
CTR HN 0~'~"48
,
i
a
%,onw+._
VIII.InAa4Gon .......................................................
iX.Gauroiniat;natTraa ............................. .............
X.13verind 1litiary Traa ...............................'...............
X1.Kidney ............................................................
X11.Urinary 8taddet .....................................................
XtI1.Phosuta ............................................................
XIV.Gvary and Thyroid ...................................................
XV.Tatida ............................................................
XVI. Mammary Gland. hsxnti. kAtatrcJ ....................................
Raf.esnas ..........................................................
Notvrol Kitler CtllMediatrd Cytotoxietty rertut LympteomQ in
Nanutert
S.K. DatTa. M.T. GutAoMU and 1.1. Taumw, Houcton, Ta . ............ t b
Introduction ............................................................. 1/o
Mauriah and MstAodt ................................................. 112
Rawlu and Dnau+ion .................................................... 113
Natural Cytotoaie Raetivity is Hnnsun ............................... 113
Tiuua CisttiEutioe ot NK Calh ........................................ 113
Ap Rat>a we ot NK Reaaitity ....................................... 185
Eti.cct of Radiation, Crdophap4mida and Qmptrus Trnrunaat o. NK
Gdl Aairity ....................................................... 117
ER.aa ot tw++or Gro.M oa !tK Cd1 AaivKr ........................... !tt
Contlullim .............................................................. 1 n
Raf.w" ............................................................... 190
SuajaetInda ....................................................... 194
~
