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• 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. retpacti•eiy: 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 Uvioe•wukly 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 20••33% 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 DMiA•induoed 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 GlmmK•Gut~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,IOdarKtM1.1,2•bsnanthrfa+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 1•1'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-dimnhyt•1 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 68•i

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 DM3A•traud 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 FWta•3as 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. Tht•u 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 odi•mediaad 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 wtnor•bnrinS 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 have•given unsatisfactory responses and especially the tongue has proved resittant. FWitA at ol. (t2j have developed a method which proves 100% lowful ir rwj- eziw- a•f!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 N•nitroso- heumetbyleneimine, dipropylnitrosamine, alkylaitrosamine, N-aitroso- methylurea, 2-hydro>;ypropyl-N-propylnitrosamine, and n+ethyl-N•propyl- 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