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tk /t, Chemical Carcinosene.u in Syrian Hamuers Ny The histolo{ieal eAanses induaed by NMU In th. muara of the smaG intestine diRar.d from .rAat has been desaibed in sns"ie intestinal adenoareinoma and prolUtxati•st Dcitis of Syrian hanuters. NMU produad al+sration in the vitlous areAiunurn and cyto. logictl change in the absorptive alls. Thers w as marked shortening ot the villi and redueed thickneu of the muco,a. Tho vill0us absorptive od4 wne larip and e.boWa) witA «ntrally placed nuclei.' (Author's sueurury.) Hta.ct (71 J: While N,N'.limaMylniuosoucea aused tsawoqe+tic arlto~ h rua aud tslali6nant thymomas in mia, this supttanot,when given to 34 Syriam haaewvf of both twa .eighin6 90 S!sy m injeeGon In doaea a(r0 to{/kt body .*.pt, a+..d (is 17-)1 .eeks, avera6.21 weeks) 23 pusnatr odl earonauew of the forw+en,asA (b6'.:). nans~ as,.ry tumors in 79% of the fsnula and 16% of utarint oervis tMnortl h.or.at.e tuators (adenowrsinomas, 11y.), cAolanpioaranorna of tAa 6ver (24%) and wbatuwus t+ar• comas accvrred in 6%. There were also OeniS,e averaoutt Aerrwpomat of t!W spn.n, hyperksmoais of the foeatom.cA and sane tssa of liva sirrAai.. Hww (72J: Carcinogenic eReta of N.N'dimahybwtrosouma (DMNIA om mia aad laurnsten was studied. Rcpated subrutanaous injeaions of DMNU ravlud in the iadua tion of taali6nant IympAomua with an incident.e of 100% in adult C)H!M11/Ki mia ano ieWuad malignant tumors of fonstanoM, mammary gland and utsns .,Ih a high ieei. dcnet in adult hamuera. Control uumals aho..d eo pet)wlo6ieal ehanps. Eleettoa asieroseopY revqled the pnseena of mtxies type C ras panido ;a sane of the tissues eaaminad. Many type C virw partidea .+re found in a transplant of DMNU-i.duod mdignant lye+phonu. Some type C vins p.nicla .ae sLowe in matGpnant lympAornn and lymph nodes of ineligrum lyrnphornrbeving mice. A very small nwnbn of type C virus partides were ob.crveJ in thymw of oomrol mice aed bone rsarre+ of a moli6nast IympEoma•barfnS movst. A few pattic)a, quite similar to murier tyyt C viwa putides. Wae deteetad in DMNU-ieduocd nummory adeeonrtinoeut of hamu.r. No vinsalika panfc4s were saen in mammary glands of control Rsntattn}, WhetJwr tLtaa pvtieb aro merely pusentcn or are playing a sipdkset rola in the earonod.n.ir M these wmors rsnuieu to bs detertnined. Htaow.r.L Gf3I: TMes Reupt ornew~borw luoytas ntsi..d a sirtdl* as:+Jeaioa of 0.2, 0.4 and 0.6 mg cycssin/6 body weight within 24 M aMr bint T.o droua ot adWt hanrters aeh received one doae of 0.1 or 0.1f m=cyosieVi body we+6At by stomach tubc Awther three groups of adult hanwers e.raived two to rwr dowm of 2.1 .y ernr.ie)6 body weigAt by stomach tube at ietarvab of I montA. TAers was no sipti3nnt difRertnat (s tlft Isadence of tumon bennw m rlorn ud adult hamsttvs rocsiviey a ainih adnvnistrstion of trasie and ba+ar aduh s.rrtsten reot:ivin6 s+n61t and rapeuod administntions. Hortvar. adult haesmt r.aeivin6 the larM unpk doae o(c)casis showed a lipher ineidmas of tumoes tltaA taoaa t.oeiv~ the amaUer single doss. The most importanM ctanles induoed in lanwees with tyonw ..a taes a the li.er and eonsisted of proGferati.e dunpa of t)tr iraalseptit bih duaa. M. dra euainomaf v.crs aoducsd both in newborn and adult hamsters. Although Aepaoaeltntar oueinom.a vs as readJy induoed as bik duet arrfa+oenu in newbora Aaauters. lspatoadlukr ear- eieonus weae not found amonS adult atsimals. Eight li.tr tumors induoed by qeasia wt truxplanud, and 6ve asmplteubk tumor lines w're successfully esublitAed: Four lines originated in intratKpatt bile duta CTR Mt~ 0~'~~~"~~

Hanunctu IS0 arcinomas, and the /lftli originated in an anaplauit: nrcinomt. Owwnably of liwar11 oriSin. Kidney and intestinal tumon, aitidt .ere frqueatly induced in rau by cyw;n, wete observed in a much lorsr incidenae in hamstses. Ho«nnteca w d. (71iJ: Invasive adataordnoea of the tlandulu aomach wu induad in 3 DIO • 17.20 inbred Syrian huroten by the adntiniuration of I ppm N-nitrosa• dicthylamint' or N-niuotodinxthylemint ht the daintieS wta, and in 2 210 17.16 and ! 810 72.29 inbred Syrian hanWaa by p.ap ef 3-prtbylehelanthrsne In oontrau, many other similarly trqted inbred Syrian hanater lars did ta( desslop areinoma of the gIandulir stontaCh. The glandular MonHChf; Or rats and n1iOt are rQfiftant to potyc)tlit hydroerpen areinofsnaa; hotreve., the glandular stomachs of taertain inbred Syrian hanuten develop adanotareinonta after polycyt:lie Aydronrbos Pvar. This work dan. t>futrated the intportance of genetic factors. Ho.ovaen n d. ( I p): Seo p.K IOS. So and Wn.roct (176): 2.2'•Diatrihylj-astinoliphenyl (2,2'-DMSA) was adminis. te:rod subcutaneously in dow of 100 tnS/kS body sisht to Syrian golden hanutsrs. Of 20 han.uers that lired over 158 days, 1! (12 fas+ales, 3 tnab) devdopedbkaJJer tumors. In addition, 2 adsnoareinomv of the eoloe. I malignant lymphoma, 2 numnyry car. einomas, 4 pranulosa.tMa eell tumon of the ovvia, and I spwmous cell arcnnoma of the skin wsn found. The nKSn tasmulativo dotr and dtyf reouind for the indueiion of bladder tumors were 2.400-2.700 at!/kS bQy.eyfn (I6o-a03 ntShnimaU and 260-)10 aya. We belias th's to be tha ant t.pat of Nn it,dtxtien ef bladder tomon in Syrian Soldts hamsters by 7,2'-DMlA. Smv.ar ( I t I ):T1n tok ef a Sentt, tilona or bt tanbination, ddeh produce adeno• nreimmma of the stornach in ssperierntal aninult is ravie.od. Thtst ineludc 3-methyl. Motanthrons; N,N'-2,7 ; N•2-Auorenytacsumidt: irradation; alfatoaieu; elaiomyein; N-mahy4N'-nitraTr-trva~oSwnidier; 7,124imstbylbuuamhra- oene, and N.methyl-N.nhtoae•N'roetyhla Ineidaeotr, aitria for diapasis, and diRtrent routa of administntion in n+ioe, ratt4 SuiMa pip, and bnwen an diseusud. 7Ae ob- ter.ations in apsrimental aeinuls am n1.Md to tl» Otebla+e ot hueua nnoir. (Author's abst»a.) Tont (ItSJ: Ten suEeutaneas iqjaRiona of I try trethan/i body reipht wers adminstarsd .skly to Syrian pldal hnmunt at bitth and aduh aIe. Significantly higher numbers of foratonoch papliotrri de.doped M aa4nt,h tNt btpn to reol+re urethan at adulthood than at hirtle, tevsn though tltere .ern similar incidences in animals having this lesion in both ap,e groups. On the other hand. appreciably more intestinal tumon were found in those hanrtera ttartinS to reaeine the tnatnrm as eswborm than as adulu. In addition, dermal melanoeytonw and thyroid, Ia+S, and some other tiaue tumors s» iebuoed without any apparent diReeena ht Lmidmar in the mo ap Smps. In contrast to the effect of a single nreieapenie dow to .hieA oNy two tss+w nspor, 4 d- wwa1 additional tiutia develot+ed tumors wha elalksnpd by r.pntod injeaioro of wstnan. Eithn their ttaTon6enio thrahold doie rY higher and they tkaded pniodic stimul~ or morphotofie and functional dsvebpnrnt ou swt at an appropriate stapp for tunar induc- tion at the time of the single injection. The possible sR.a thal tIM ap of the host has oo tumaipenms s discvsud in light of the teulu obtained. (Author's aEuract.) Waasauaeta (I91J: Colon cancer m are almort lkrtaroly If induced ey a+nra+- etenW facton, probably consumed with (ood. Exspt (or ana lrpd of hunsun, ooioe CT 1'`. f t N 0 42 6 3 8

is Ak CAemial Carcino=cnesis in Syrian tianwen 11t • anar b inheQuent in taboratory or domatie animals. Reliable induction of eolon anev an be aehieved with two broad dasses otehemlah: (t) derivativa or )rneshyt.4amino• biphenyl. and (2) dcrivatives o(1.2dimethythydrazine. including the plant product e)essbs. Somnimes an unknown ingredient of bracken fern auses aeat or colonic anoers. Yhe nrtabolism of 4-aminobipheny I derivatives invotves, among other eseps, N-hydroq'tation, eonjupiion of the mctabolite with plucuronie acid. waetion of the conjupte in bile, liberation of the free N•hydroty compound, the postulated astive imermediau, by apian of tsacteriat (lora in large inteuine where reaction witA sipti(kant tiuue, esU. and srotav. !v eMments aocun. After oral intake of tyasie the aSlyeorr u+ethylasosymMaaol ie likewise freed for raction in colon by bwterial enaymea. 1,2•Dinxthylhydratiee yields alosymethane which is hydrozylatad in Gved s:onjupt.d with Slut:woeie atid and aeeresad in bile. apin to be split in gut with liberation of the aaivc meUtytatwtymethanol. On Ae buis ot these models. colon anar forntetion ir man nuy involve: (1) inaestion ef rvn• pla c~reinoaens with dict, with liberation of the ative agent by bacterial .ntymw; (2)intastion of proareinoacns. absorption, sntabolism by li.er, ueretion in bik, and trsing of active a{mt in Sut; ()) production ot active agent by f>•eteriwl fkn In prt by eonvsrsion of seket food precvrson, and (4) production of a myeaoaia by an ieuuiaal tt+icroorpnism. (Authot'a abssrut) X. Liver ond ailiorr rrecr Carcinogens which induced adenocarcinomas of the bile duct included 2•acetaminoAuorcne (also in combination with MC in the diet) (36), N,N'• dimethylnitrosourea (71 J, cycasin (73j which, in newborn hamsters also caused hepatocellular arcinomas, and 1,2-dimethylhydrasine (l,2•DMH) (Id6), which caused bepatotttas artd liver oell prtaeottus,. Sometimes it is diRtcult to distintuish the two latter lesions from each other, and one ease of a benign 2•acetylaminoQuorene-induced hepatoma was teported that, upon transplantation, was found to be highly malignant (17j. Protein binding of azo dyes has besn compared in IC and C3H mice, and hamsters fed p-dimethylaminoatobestzetne (22). The binding of the dye was found to be somewhat related to the tozieiry of the dye for the tested animals, high in C)H mice (susccptibk) and low in IC mice (resistant), the resistant hamsters being intetmediate. Nitrosamines, speci6ally DPN and ahydrotrylated dipropyl nitro• aamine, as well as MPN (S) induced hep.tomas when given subastaneously, but only MPN caused also esophalleal squamous nrdnomas. WlrscHu (t97j studied the biochemical eRet:u of s.e. dosing of hamsters with diethylnitrosamine and found that protein synthesis and aryl hydro- carbon hydroxylases were affected differently in liver and lung. It is of interest that hamsters appeared to be more raistant to the L..M i R i' --AItr 3 0 42 6 3 9

b Howauaca A 1 ® hepatocarcinogenic effect of aflatoxin than rats (67J and that the only tumors• produced in hamsters by aAatoxin were adenomas and papillary cystade- nomas of the Harderian 61and. It is unfortunate that tbtse ttudia were done on unspcci6ed hamsters and that it is therefore impossible to know whether the described resistance is species-spet:i6c or genetically detetmined. Other substances found carcinogenic for hamster livers were atethyl- hydrszine (1881, and 1,2-dimethylhydrazine Siven.in the drinking water (1 i7J; they produced, respectively, malignant hiuiorytomas or hepatic an=io- sarconus in the liver (as well as in the lun6, muscle, heart and pancreas); 2-hydroayethyl hydrazine in the drinking water caused bepatomas in ham- sters and had no carcinogenic effect in mice (169). NAwsAtct fr at. (124J noted that hamsters were resistant to dietary be;nttne hesae6loride, which caused liver tumors in mice. Rats also failed to respond. Gallbladder carcinoma was induced in hamsters by truans of dimethyl• nitrosamine combined with cholesterol pellets implanted into the gallbladder (13 out of 19 animals), and in I out of 16 anitnals receiving only DMNA. Diethylnitrosamine with or without cholesterol pellets caused no tumors 1951 AirMOn er d. (S1: The metabotie activation of ahroa aafffettnda by a•(tydro:ylan tion ie .R(1 keotre. To explain tM t+natpatad eabytatioo obwvad aMr the adminis. tration or rarioue nitrao compounda to rattti additipW tKtabel'stn by `.Aydroayl.tion has been wssated. Experiments were therelore desi6ned to eompare the esrcinepaie eReet on rata of di-n-Oropyinitroumine (DPN) and ib Deualat.d nrubolites, bbYdrosy- propyt•propylnitroaamine (HPPN). (OPPN~ aod u+stlty{• peopylnitrosamine (MPN). Each e:perimenu) aroup eoas'stsd ot 10 arM aed 10 foe+d.12-wk-otd Spra6ue- Dawky ratu. The aninub .we iAjacted subatannow/y ona a sk for the duration ef life witA doem equivalent to 0.2, 0.1 and 0.0! LD„ (LD..: DPN: 1.417, MPPN: 1.273, OrrN: 4:4. MPN: 106 testkS b.r.). WiMin 6 e+oetAt of be=+ntini tbe aporinw+t, aptxo,tinutaly 30% of the rats had died. All compounds had induoed tunan or the liva arta S months of treatnxnt. TM neoptaun..rs tepetpra and tttprataotuular ar- einomu;. After 6 months or treatnKttt, tumoes ef tAe e+oplrsut.ots ane onh Lt animats raceivin6 AtrN. HicatoeiaUy. ttwe .era squamous oW peOfttoeaf and tuntini:ir+a squamous ail carrinomai. Thw preliminary rewlu indinu that }hydro.ytation tu+d qdfsepuatt aepe do not alter the urcinota+icity of DPN. Similar mudiawith Syrun golden lunrten pve aimilar retiutu. The neoplauro induoed in rats by aHPPN and b-OPPN desloped in Me eanr orpne as after DPN applfntion. Ha.ever, aopAa6sal tumors in ratA altheuah twn in otAes aperimenp, h.ve eot yst besa found artsr tr*sunatwitt1 tAe "Pdronr4ted eom- pow+ds in out aperinrnts;. Dectiarr.a and Mevwrta (221: We studied aso dye binding to proteins, and at the wme time atoraluctase and NADPHsytocetrortr c roJunase activyks in Me lirver of IC and C3H mice and hamstern fed DA1(~dimetA~batinoarobenaene) orer a long pterad. Sauhivity of C3Ff mics to the toztic effecn or DA! and raiuano of IC ntia and ham- V T R VAIN 042640

Chemical Carcinopenais in Syrian Hanwen 133 sten wers tronArmed by histolupiol wminasions. After 3-3 wals of DA{ fenlinp, tM amount of protein•bound aao dye inernsed pradually up to 6.esks, then remained rwrly constant. In control animals uoredut:tase activity was Mv times higher in IC miee than in C3H mia; activity of hamsters was intsrmediate. NADP1iaytochrtrnr c reductasa aetivity was nearly the same in all three poup6 and was in eo way related to atoreductasa activity. The sensitivity of C7H mice to the to,ae efteeu of DAS eoaJd be eaplained by tAdr weak a:oaducuse anivity and Si61s level of aro dye bindinp to proteins. Ott t6a conuary, high nzoredueuse activity iu IC mia would allow anosicauon of DAD aad prmnt or delay its toeie ef1'eets. Resistana o! hamsters oould be linked to the amll aaaunt of protein•bound aio dyec yet It annot be explained by thsit weak umredut:tau aetivity and probably depends on other mwbolie proasse, .hrch have besn oonaidend. 8r.oroTO er tl. /76J: Sae pap 141). Gtasu er N. (4t): we reyon a highly tnuignant transpbntabie tumor. derFved from the )iw of a h:mster fcd 2-aaty4nunofluorate that did not appnr nsaliptans : the donor. A piaae of liver tiuue was «anap(anted into three ntck wnlutE hamsten; 2 mentAtt bter, all three developed mana at the site of trarrspiantation. The neoolasee was a Mnr multinodular white atinss, Ibstolopially characteristic o( scirrhous comnoeu. Hannsers with transplanu of tumor tissue, oaU susqention, or all euqure all developed a AiShty maliznant tumor. Thosc with tranaPlann of soniated eelli, piaoes of liw from untreated hanwxs, ard saline injections did sor develop neop(astie powhs. Tnnsplonts through 30 pattsapes .ers viable, hipltlY tatGptuu, and maintained the ofipinal wU type. 1iu.ous 167): Allatoain adminatend to Syrian haeutas, intrapastrioUy and intra. peritonnlly, induced lesions of the liver, kidney, small intestine and periodontal membrur of the incisor teah. Tumors of the Harderian fland Aad tw histolopeal p.utsrm, solid and papillary cysudenomas. Eaithelial nau of Maluses.vc naed ut the psriodontal manbrut<. Focal hemorrhagic t+eaoais, bemoaiderin depoaits, sne=afoeytosis, aad bile dut:t pra liferation oo:vrted in the liver. Tlr rmal Maion was eharactaiaed by eytomeialic drstp in the proximal tubula. Histologically the small inteatine revealed alteration in the rillout architecture with marked shoneninp of the viUi and reduced tbicknas of the mucosa. The villous absorptive e:lb were cuboidal with oentrslly placed nucki. lisa.rt [11/: See pap IH. Hieow a d. 173): S.e pape 14f. Kowsytwstu and Tooo (4!): Hattwas aith a without wrpcally implanted intra. dro)aeystic eholesterol psikts wve Siven eardnoaen diethylnnroumine (DEN) or dimah. yinitrosamine (DM Nl, dissolved in dri.kinE water. Eapowaes lo ehese earcinopero lasted from 1 to 12 weeks. No pNbtadder twnon were found in DEN-tsoted banutees, with and without intraedtoleeystie 'eaaerintensal uona'.1e LI'X% of hanwers eaposed to DMN and having pllbladda pelkts, adcnoort5nonua were found. Only ane pubJadder tturwr was detected in DMN.trated aninub who W t+e pllb{adder pdkt. It w concluded t)ut 'eaperimental pllbladder stone' eNtancsd the malignnt tnnalormatwn of pUbLdder mucou in DMN.tnated hamsten, tt tw considered proboble that d»olaw of bile duct and pllbladder t9tthclium observed only in DMN•trnted animaJs retxesents a premaliS• nant lesion. Presence of this prerrtalipunt lesion atsocuted with nonsl+.c,lk irtitation of ptlblaJda mucosa by a'uone' nuy be considered an imporunt euolop,cal faaor con. tribuunt to rallbladder rtulitruncy in hamuers. (Authors' abwset.) Ci R Hi 7 0'°'T 2a3 '°T i.

, i .ti . J Howsuacca 154 N.c.SAct er .f. (126): The tunoripenic eRecti of a dix containing the s-isomcr of bensrne heachloride tu•HHC) on the liver of vuisw aniaAab was es mincd. )t waa found that s-DHC indueed Iiver tumors in mak and (smak atioe but eot is nu or hansten in the present observations. HistoloSieal ehaases in the liver of mioe induced by a•AHC M ert also much pestor than thou induced in rau or hamsun, Male aaitieuflt.Kre more wKep. libk to the tumai6snic action of a•!HC then feeulet. As+onS diQaeat etrairo of mia, the DDY showed pnwt wscsptibiliq and the CS71L/f nhe.ed the least. Induction of mouse liver tumorf by a•1HC ras not inhibited by ooncomiuWlt feedinS of /-naphthyl isothiocyanate of,rby,arosyeropioOhenone. Howsver. 3lnethykholanthroee sliShtly ier faibited their indurtioe by a•iHC SNt.usu and Tznt (1691: Solutions af 0.0111% 2-hydrosyethy0tydrudns wsre S1ven condnuouly in the drinking water af 6. and f-Mekeld tnndombrsd Syrian Snlden hamsters and Swet mse for the remainder of their Iifesima.le treated hamsters. 6% of the fe+nelet and 10% of the males develoeed hepatortW, whereae among untrpted eon- trolt the eortosponlin6 ine;dencs.ras 0% in tl,e fanakt and 1'K in the males. The chemical did not increase the incidenes of otha tumors in hamsters nor did it result in a dcteeubk tumori6enic eRat in mits J•rtyd. o.rahylhydratine iewiJely used te induce the lbwerins of pineapple plants. tn .ie+ o/ the earlin reported tumoridasieity of thit compound in miee, the sisni/ianes ef U. prwent findinp it ditetirsnd. Torn (I1t6J: Solutieet of 0.012% hydraefne wlfau, 0.001% t.2dinuthylhydntine dihydroehloride, and C.!!( i/aicainie aeid wt Siva ooetisuaufy in tM drinking water of 9-. 7- and S-wekeid randomly brsd Syrian Vldea hamsters for d+e ra.rinda of their lifetime. The eoruump+eo of hydrarne eulfate and 'soaioeunie acid .ata .ithowt any sirnifkant arc+no6eaie .nien, .Atite 1,2dimethyfhydrstine dihrdrotitioride induced an6'otueomas ol the Nsod ..ult .ith iaeildeaos of 19% is f.malee aed 112%ia auMd. In addition, :t produced as apqe+riab:e aurnber of twnon ia Ur eeewa and liver. Thw Mdin=s dnrfy show that the atciaoesinie eQest o(Aydraons tmlfats b:peoes- dependent. Resulu abe n4iou that the .arioul orpnaro0ie actiar ot 1.2•dimethyl- hydratins dihydrothlor ide rhen administered by aaOtMf routs is Iha tims t;yecies could possibly be due to diffarmt nwbolk psthwsyta. . Torw (117): Studie .ae mufe on Ute aroepholoSial chtrscteriuita of blood .eitd tumors induoad by the o.s. lifetime adminiaratisa sf 0.001'li 1,2-dinKthyUtydra>Jns dihydrochloride in Syrian golden hamsters. TM laiotr w.re ehs;eifled as anSiaaroonw. They em+rred ia 19% ot the fsmalee snd 82% of tb mua (with detns<in5 fnque+ky) in Gver. lunp. mtueJe, heut, and ponaee. crya, light. and d.etren etinptvpie and lituoclNtt+id) inNSligations were perd fornxd on the tumon• The .e»ero+eopie and light microscopic study t;ho.ed the typieal appcarana of ansiararoenn ean0oud of rouad ot eloRpted polr~nal a.opiutlc endo- Ihelial alls which fornrd weytsr oens aad delu. The hatod+emieal oork included the deteftninili0n of eblkym IM1LhMr. ioniRnd irpa. 001 yYethtlRdh slyoolie fatty aeid eauerK. end altaline yhaphataet en:ynu netivity by the ksion. The fonnauoa of reticulum sad wn+sd iron was at"bk, while the amounts or the sairty of the other thra t:ubasnaw .e.e fubuantiil. EUctron microecopic aamiaetion revakd the ultrafvuewral daatit of the .uneut eomponenta of the vaeeular lesion iucludin6 prrt of itf developmental ata0r. Heme+rluaie areas, structural eJuraeteristia of the an6io- tr+conta• maligrem endxwal odl nudns.ith duomstin arrsnSaroau, and its cytoa COf R { f f 'f 04.2642 r

Ctrcmieal Caranopenais in Syrian Hanrtus 111111 platm with orpnelks, intratuminal atl eurfaoi, and contaet between neoplastio endo. thelial calls art deseribed and illustrated. ToTM and SNwizu (liq: A 0.01% solution otmethylhydrazine was aJminiaend daily in the drinking water of bw.ekold randomly lrsd Syrian golden hamtaen for tAe ssmainder of their lifetime. The treatment pve rise to malipunt hutioeysomas d IiW.r and tumors of the cacum. Malipunt hiuiocytoma developed in 32% of the (e+natea aad ia SN% of the mala whereas among the eontrob no such tesioer were t.an. The iasdeeee d tumors of oaeum was 11% in fematn and 14% Is maka, eompand to 1% in the aantrols. Macroscopic, light and electron mieroscopie, and histahsmital invatiptiom of tha liver lesions thoWed the eharaeleristio appearana of erliptant hiuioeytenw. The hir toloaia) involvement of the tiswa by the tumors is poaented. The nne w>,ettrt of the eniiSrunt hbtiocytonu, the nuclei, and cytoplasms with orpndls of the tumor aW ars deseribed and illustroud in deuil. Methylhydrasine u a rocl:ss fuel component, and soer of iu drrivativa have baa propaeed for use in usatinS anain human onars. Dr+ousa it has leen t+howt+ to produa tumors in mia and now in hamsun, t+recsutiont should be taken cvetesrnini )u ttle. Wrncut (1971: (I) Syrian Sotden hanuttrsWere treated with a single wlatatrotr dou of 200 mS DENA/kS. In the Iiw Me treatment produced a eipninesnt and aary inlulwtion o( the incocpontion of otntie acid ieto RNA and of tertane into prots+n. DENA also lowend basal and 20.MGetimutated activities or hepatie aryl hydrocarbon lydrosy. tase (AHH). (2) RNA synthesis, protein synthesis and AHH activity wsre atw e.aluand in the lunp or the same animals. In this organ only protein synthesis was aRaned by DENA. but not RNA tynthesis or AHH activity. (3) The Incorporation ef Mymidine isto DNA was inhibited in both orpw earty after DENAtratmert and increased 2-) days tatar. (4) Althoulh DENA. injected suheuuneouety, aetumulaW in liret and lung in to:ioobSf• eally acuve amounu, the acute OiocEonieat reipoires e+r the h.e orpne are not ideetloal. xr. x/dnry The induction of bilateral rsnal arcinotsta by diethylstilbesuol (DES) given to male hamsten has bees eonRrmed by many investigators sod this induced rtnal tumor is now being used in its transplantable form for chemo- therapeutic studies (as s model for ehemotherapy of advanced huntsn renal carcinoma), with S-Auorourscil appearing to be more effective than cyclo- . phosphamide, dactinomycin, mitDramyda and viob)astine (23J. DES di• methyl ether also induced tumors, wherw DES toonollucuronide did not . (98J. The model is also being used for ensymoloSial and immunological investigations (11S), and in sophisticated investigations of its fine structure 1102, 111). Such studies were concerned with glucose 6phesphate dehydro- tenase (29J which fluctuated during tumoritenesis upon elearophoredc study and was found by Listochemical studies to be incrused in tumor tissue, as was isocitrate dehydrotenase. Succinate and ~-hydroxybutyrate CTR H N 0 4 2- G 4 3

I Ha.nuRuu ISf dehydrogenase activities, on the other baad, were more intense in normal tissue than in tumor (122). KtRt:wAra 1901 found that none of his DES-iridutxd kidney tumors was ever as hormone•independent as a transplantabk, spontaneous kidney tumor. Isoen:yme analysis may provide a means to distinguish between hormone- dependent and -independent DES-induced renal turuon (2a). Estrogen receptor studies have also bess carried out in thest tumors (107). MtTUtit (116) claimed that eposidation of ths atilbene double bond presenu a major pathway of DES metabolism. Certain subt)e differences in estrogen binding by estrogen-dependent and estrogen•independent tumors have been ducribsd by Ktso er ol. (d9), and biochemical studies on hamsters bearing atrotsn-induccd kidney tumors showed a deerase of hepatic 6lucuroayltransferase activity toward DES in hamsters treated chronically with tlut hormone. - Chetnoprophylaxis of renal tumors induced by DES lus been achieved with 2•bromo4trjocryptine metbaae sulfonsts (S4j, which appeared to act via the pituitary. In tetrospxt. it is deplorable that the powerful earcino- genic sffect of DES, demoutraud conclusively in 1949 (92) upon the male hamster kidney, did aot prsvent the clinical uas of DES which led to so much tragedy through its intrauterine eNects upon renal anlage tissues, which in shared by the renal tubules tusd the va jinal wall (Wol!liso duas). oa Kuwa+at.l. (1a1: DES•iedwrd kiQaey tun+en..n traarpl.nt.d into the at titsus of DESStr.st.d maM ltverwas. One ar'niaa eeW •ana Ytjiaad and tueroes allowed to grow for 30 days bdore tAft aaimeU rsotivad Lp. Injaetions of striM aline (control) erery 7 days or 0.15 nqlkSl+vsk of .inbtaaiee. f aWke/dar of eyeloohosflhamide for f days followed sy S mSlka/day ror S days of etitlrfmtsin,lS aylkgfdar o(S•nuoroaracl ror. ays, then 7.5 eulkS oe atternate days ror rour dosa t1+as dosage kltsdwlea .nrs ehosat b.uws they aoreaspad to dinintlp r.oommatdad daats for bwnam. Cytosaa and vincaistine nusad no tumor tnhieitioti f•ftwouraetl pq tM tt+at marked tumor inhibition and caused aipti6antFr ieer.s.d tauvivaL MiUrunye.ia and daeunoe+yata inhibit.d tuawr growth but did not aaat sdrvML Dooca 1:!): Several in.estiptars InN ahown that changes eoew in isocn:yme aniri- tia of laeuta dehydreaenaw (LOH) and ducps•FphoapAats dehydrota+u+a (GdPO) as tiuues become neootauie Ae+ytsatids-iel atacaophoretie studies of two Syrian hamster tumors havs demoesuautd eAaeM in ttte itoeeayrets Paturnt of LDH and G•6PD dur- inS tuner oroarasiaa A DES/tstewrar•induad aomt aland tumor devslopa• Me typical LDH peture of tealipunt tkus (Ai=h aonadttratioa o( tM ato.et n,ovine Yaen:yme) as it oropares to itu Ana) arcuwtie aats.'!ha GiPD isoenry*•+e pattern of a DES-induced and DFSdepa+dent tsar) areisoea diRsn frorn tNt of an autonomous Mormor,eJndapsndent .ariant dsri..d froen It. Siaoa aAW awop+H induad tumor of ths kidney of ths Syrian hamuer w/kst dat+aibad. aerertl kramoae•indepcndent autono- eroua variants and oes sooauneou reoat tt,mor ha.e aOpund ie K'uknun'a tunuter L.r f f"',. f t f'f 0-"f' 26'."i. s..'.y.'

rl Chapter 3 POTENTIAL CONTRIBUTION OF INBRED SYRIAN HAMSTERS TO FUTURE TOXICOLOGY F Homburger 8ro Rrsa:•:^. I^.. :~:r INTRODI'CT10% I T-e se ..'t,r, _. 3 s.e::es c' 5n;-na; `or .:t.,_,:¢: :est'^g -is ^tt., : A,,. :n a ~:.e.^..... _3i.s T J"~s .'3^_C'S'1 :I •~':CJS ,.]sSts JI .:1,. ":3:...3 s in `'.;mJ'1 i_.'e::s Jt;J :J s:3r:^ !Jr '~3t s7e;.ts Q! .lntr.,31 tf:3t h3rales !'he :t,1ss JI si^st3nCQs :0 ~C ... ...e sl-e •^3r•^e: as man P e~wus:v. se:e;t.vn ii 'hie jr. rr.i!s 'i tie -.a-- ~een 3rDt:rary 3nd not mu,h ,...ierent frim :he ^et!:cJ Et-,;.::3n . -3r3o`Is ~Ar.o. xhen .:o ^:an. ~i .-.eu ..~ o :as:es i+:•.:"e.~• . . J•CS :J .'J.J1t eS f), j :r3 ; e•:ed oi un;e rats h3ve been :he f3vonres oi tix,;olo¢tsts •'esprtc a h:v_h incidence ot disease and spontaneous neep~asms E.en now. r:ts :o h3ve wide tox(cu!ogt~ use. espe:cj.ly s(nce pathogen•iree ar.,rn3is tiase become readily available. S1tce, too. have .een a irortte. espe• .:a;l% oi etper(mentil oncolog(sts. In contrast to other rodents used in eiperu^ental pathology and toxt• co!eey srrt:e the dawn of biomedical research, the Syrian h3mster is a new• corner to t`:e laboratory The tirst s.tld Syrian hamsters (tiletocrrcrrus aurerus) were captured in 1930 by Attaront (197:) &nd successfuUy propagated in the lab• oratory Through Adler's tnstit:,te in Jen,salem• they iound their way tirst into English and !ater into American research institutions (Yerttantan• 197:) Today, :r.ere lt;an I m;llton Sy nan himsters are so;J annually for research purposes in The author's *ort tn;iuded in :hts rc~ieW Wos supported in par• t. ISPHS jener.l research suppon t»nt SOI•RR-055:5 tDt~tuon of Resejrc!t Ij;tltr es 3nJ Resour.est .nJ :scar,h su^,por: Erants CA •I3:32. CA•:SS33..nd Ca.•I54:5 (Niricr Cin.cr Irsrt:.rt.r end in porr, by Bto•Resear:n Consuttants. Inc . Gmbrrdtte. Masucnu.c, . 35 (..« -rR f f { "'f 042645

a the 1:+::ed S,-:es j.one. Howe•.e-. :n :•: rntce and IS m:i:lcn rats used euh .e3r In \- han^.ster sail constlt;:tes a necie:ad :r.lronty' IT F n ,s•:: :o ,reups •oi :nlcl.e and tai'Jabie Jses of -Fe ioiden ~Jr^s:er. .: i reierences tTao.e I ). T>BLE I Ln,que and V.:wtve E1tper•:rer.:at Ctet'•:r :!~e Hj-+s:e^' 1 Tirnot }ro.:h :n •ne ntea cr'h ,on^t•:~IS an: b..•.rt-zn . _ Srl.en. I't6I, Chure et al . 1952. J utten .nd L.tt. 195': Lerrlon e: a, L-•: 19Sa P 9 1 .t 31 . 1 $.). htterson er al . T•inscrzntarron cf -wunaral anJ st jJutt ^t.uet :n : ttt ^ouch •H~r: r: , 1 Ye-,inran. 1954. waterman and Uohnus. 195:1. me:•i rP:-r. 195'1 :..n - :9!•1. Re.n,rt :t A . 19bOt. pe-c•ru (Hou.e ct al 'aSt:. :. SAc ia6:1..•,rnr.onrc cc?ranrt 'Smrs:r and P3rt. 1951a5 t. I :J•r'::r :Dr:rr t,: •P- C.fcrrmcnrA .atcrnn;t:ncars in ncck ;ou.n IGhaduilY and til-r,an. :y.; t!: s I u61 . SzllcY. 1953. Snu6rk. 19f9s + T:inblanu•rnn ol n•,rma1 +nd%or rnaht:'lrnl Irtwet •n •rtes o:'er :`An ;`:eee ;,.... sirn IAJamt. IcSR., 13. 1Jtmt el jI . 1956. I9ulrro+m et - 'ab -r - S T.•."+ ::antri,nu:ron 'Cab,%rn. 1960. MYets and f•anajan. :iSS. :4:':: ~ R•::c I~S91 ~ H •~1 `~r -lrtsrtNce al slu-I.et r^.Jo•nnr''a %usrol::r:e Dc a-t'e . . - ... .•:r . A;,er +r.. T'aoCOr. 14)1 1. :rrv+••sc'r;c • >.le: :9a' f. .., . .. :. .. . . :4+Sz. os. :c,a:oso•!fcr+t 'Crarn tr.,t bcncc• :n. I:+• S.-:..r . • . . . ,l.ar.,, 'a+F, ReaJ. :95I. StunaarJ. l9+cr. :•,cn:•!r:a d:,s 3-..: -.,..... +c+ H,hes srd Ak:rt. ~95:1 . $•...tt rn .vlrpt> nd ~ti 1 on~, 19!+r. ,;+!, U!^nr. et il. 19+0. t-.•,1 , 19a1 c~ ::.t _.:r:;t R:a:t-. e .-J C:nn. 1944. 4+1 i.lr. Sr Lo.rt r•r:r:i ot,nt •Br,,un el 3,. E?+:3 . r'.r-:: S: , r ~ 0+0, P'.'tz et JI . 1 4I:. SlcoDrns 1'!J Lc-!an , =+91. :A -., . •c :,N ,I .• ,io er •I . . i~:a '1 •.,Orr•-.0 ':.ia : n . .7+! i. - : r t :\1 M .. .. .. +ar ..rr `r•:r t.:a. 1:+8. Rt::.^ .. : .~53; S.~.'^ur.l~.^ct. • '~r ..•'+en %c;••ntv 'a:,er Jn t•~t'~~e~fal Irrr,.. .'1 -ce Tz.a:nr e: i :ecl to,re• J•t,/n. :i5: .. s. =i S:.:c. a,d krev+o•e:. I4S9,. ^ rrt 'w,te r+d !9eS1 ~ Ke,.zrcn n ~c,e:,ct Rc• •.scn. i*5:: .., :ri .••oT:t^^+rt C:... - : .,cnrrrnt 'Orunl ind Psnskr• Ia5:1 D%A :nC . . •.r :,'itn. loe,:r M.Cra. 9!•1. %1e,ers ;9'.v Me.r.s a-ij C't:::e: =!6 1451. S•,dc!+3-1 ., al . 1956. :-. C'1. : 'Ic<i I: he+n,:r„n ,Bro.t 1 4003 + C~:•%-eld :, L.-,t-. 'aS+ D• ~:10 L.TIn and tz*.e!:• 1~5+ \I:Lrre.1. 31 . ! .^tttmrnrzl ^N.1vlu~) r'O:N:nf ^rr':•;Or .$^•Ith arJ lZ:Ss al.:ZC, .-O:t lr4-trnj •RJ+IZnd .t^.j walers .Oler 1 3 INenlat ,.•.et ' a•^•r.J. 194: H.rst et I .349 Ae.es. .1`6 we,es 3-. b Wrlchesl •n0 Junnwn. l95'1 . ? •Repr,nreJ DY :hetmrss,on %reRS Ttit ll:•ntrr• e: Rue H' `-ac ?t.. Robinson, Ind IlYldt Ma6atnaes C IoWt Slate Lnr.erulY Press. Anus. I+t9 C/ R H/ / `.r' rr u'i..a id 7 is.P