Document RJyQ70Jmpwy8Bbze2kmvnE9G7

& /ITUS J Null 109 '71 '979 Flitaya JO and S.N .ersnoh Relationships between hydroxyprolma aerjinc and oxalate excretion m ms fad different jvais of vitamin 86. Fad Proc 3fl *62. 1979. UPPORTED BY u S Dept ot Health Education & /aifare Public Health Service. National Inst, of lealth Nat'Onai Cancer Inst 147.409 i, ET K/uECULAB biology of ETHIOHINE car. inogenesis Boren AM C Cancer Research Center & Hospiil. Deal of Basic Oncology. 640) w Colfax Aye., Itawood. Colorado 80214 (R01 CA 23536*031 ome sudsiances w-th confirmed carcinogenic actrvi, do not react *n the Ames test for carcinogenesis, d ihey do not react with DNA. Among these is ihionine which aces not react with 3NA. Bui does iact with transiei RNA The latter reaction is specif- lor a m-ncr species at iRNA, lRNA2Lys This seici r.tv implies the intervention of some enzymes ,hicn recognize tfiNALys, in addition, we nave disdve<ed that admmisttation of ethionme elevates .-ogesterone levels m the target animal The eleva-r- ,s ertracromarily n.gn. .t can be as nigh as ten- yc c aorlif.cn to tthiomne. two other carcinogens .in. |- are negatve m me Ames test, actinomycin 0 rvt inioaceiamide also elevate progesterone levels ne aim ot this research proiect is to study the noiecuiar mechanisms of th.s novel mechanism ot arc nogenesis llSv OGRAPhiC REFERENCES Kuchrno, Y and iorek. E Tumor Specific tRNA Phe Contains Two Supernumerary Metnylated Bases Nature. 271, 126 19781 Kucnino. Y. Shatma, OK. and Borek, E. yiine Transfer RNA2 is the Maior Target for LHhionine m the Rat, Biocnemistfy 17, 144 (1978) iLiPPORTED BY U S Oept. of Health Education & Vtitare, Public Health Service. National Inst, of realm, National Cancer inst S99.026 '.0219. J CDERIN SYNTHESIS VIA A CHIRAL PAECUR. X)R | Memwatd. Cornell University, Ithaca Campus, jcnooi of Arts & Sciences. Uept of Chemistry, iuca. flaw York 14850 (R01 CA 234724)2) VJrrin is the tone compound found in the haemo- - of Ihe staphyimid beetle. Peaderus tuscipas. cture and stereochemistry were established in With its multiple functionality and nine chiral -rs it is by far the most complex (nonproletn) tafenstve substance to be isolated from an insect yjuice Aside from its vesicatory activity, pedenn in stils tumor giowtn (induced chemically in Lupmus (CuS and wan Sarcoma 180 in the mouse). Cultures i Heua ceils snow a`most complete disappearance i mitosis as well as other eftects on exposure to siutons containing only t nonogram/mt of pedenn. jiocnemicai s'udies indicate that pedenn exarta its .yfctoxic effects by blocking protein synthesis and gNA synthesis in (his role it is i 000 to 10.000 ires more active man me common antimetabolites. Njerm nas also been snown to induce ceff fusion in y,rran skin fibroblasts. m.i c'oiact aims at tne synthesis ot pedenn starling i;m a read'fy available chiral precursor, D-manmtof. "he oroiected syntnesis has as an especially artrac* we 'sature the direct introduction ot one chiral *nter (which would otherwise be very difficult to jonirgi) with the correct absolute stereochemistry vodei experiments which have already been earned ^t have been encouraging. We plan to prepare opb3U-. active peaenn and pedenn snaloge tar biologi st Diocnemica1. and possible medical attainments. SUPPORTED BY u S Oept. ot Health Education A aeiiare. Public Heaitn Service, National met ol aaai'h National Cancer Inst. $21,180 2.0220. QU HYPERTHERMIA AND RADIATION INOOCEO GE- hetic damage j w,,wr. Northern Illinois University. School ot Lib*ji Arts 8 Sciences. Oept. of Biological Sciences. >Aj/P Illinois 60115 (R01 CA 23245-02) (he purpose of this research is an attempt to underHind now hyperthermia sensitizes radiation induced Stmage Mutagen sensitive strains ol Drosophila m*- angaster are suoiectod to hyperthermia treatment, 3t C tor 1 hour, and than exposed to X-rays or TMmma radiation The strains are mutagen sensitive vise ol interference with some aspect of repair, strain does not respond to hyperthermia effect rsdiation? The mutant may already nave inhibit ed the repeir Similar to what hyperthermia would affect. The hyperthermia has been shown m our amliar investigation to increase radiation induced, domi nant letnais, recessive sex-linked and the loee of tie X and Y chromosome m those broods which repre sent cells in spermatogenesis in or about irialoala. w have obtained information that hyperthermia en hance* gross defections ot the X-chrpmaeome. Thta and the above listed genetic aberrations wtd be In vestigated m 10 different mutagen aanwttv* stack* with respect to hyperthermia and redtadon induced damage. BIBLIOGRAPHIC REFERENCES: Sidney MiWer. Hy perthermia and Radiation Induced Genetic Aberra tions. Mutation Research 59 123-128. 1979. SUPPORTED BY u S Dept, ot Health Education A Welfare, Public Health service. National Irtat of Health, National Cancer Inst. S31,572 2.0221, HTW CAROTENOIDS AS ANTITUMOR AGENTS FOR SKIN TUMORS M M. MathawsRoth. Harvard University, Boston Campus Peter Sent HfllntWi V'-i'i1 mljr ton Aka. Boston. Massach* tarts 02115 (R01 CA 23053-03) involved m PAH carcinogenesis may well be invofvwd The dFrydrodiof end dtof epoxide derivatives of benx(c)acrMine will be synthesized >n the author s taboratory and mu be tested tor biological activity through the coksOorsoon of D M. Jertna, Lsporatory Ot Bro-orgwc Chemietry, NIAMDO and A.H. Conney at Hoffmann-LeRoche. The biotogicel testing will email studtas of the ability ot the dthdrodofs to be metabodcsHy activated by * cytochrome P-450 enzyme eysiem to speciee mutagenic to mutant Sal monella strame a* wen m examination of the intnnsic mutagenicity of the did epoxide and other denvattvea ol b#nz(c)#cndin*. Selected denvedves writ oe examined for carcmoganaty depending upon the mutagenicity results- The dihydrodtota and dirt epox ides wW be made available tar metabolism studies. Additionally, dimethyl danvatlves of benzo(a)pyrene wiH be synthesized to proOe the importance of stenc affects In the enzymatic apoxidation of double bonds In benzo rings ol PAH and in the hydration of benzo ring tetrahydroepoxides with epoxide hydrase. A new stereospeerhe synthesis has been designed to make available benzo nng dioi epoxides that are very diffi cult to prepare bv currant methods and will bo pur- BIBUOGRAPHIG REFERENC ;S R E. Lam. C W Taylor. H.D. Mah and DM Js ins. J. Org. Chem. jtwhppThm2hhhaiaig0geteyvvhmrsneeiitnefhaentdsenhs)pluc,tihigssiaacgohhtpnmiwatopdtsonanebeisnmuaDeottrtpeseohtaassolanisttoeftitaclkoer.etiainnimtsnthtaOesttpoeinucflrtdimamcehwalareloaidyytttrlhhemtslhsidavgiienigto<tfriissytajiahnftstirnhacteaercirnamtonaipnopsueahtnotrslistwoieehJordateUowfntgb,dtCwycmatDrhaOQen4*t,ef_s*)rW_tuwmdndeLtu-fATtdWWiMkht.pYeTaO*xlwkfntHyaPk4t.t.rJa*aPel*Lre_t.,Oeuf,o.luHPnfnR^uTR.'.LbvY^ELal.ca.itDcTMVgCbB-i'eh.If1EHlarMtqRttenWtIl.a!agUcEslr,,mt.thrAOtiLF..raWe,eoSvhhCprI.iamrrrntua,Wnnarnosk1itx/>r-oIteo9PH,nsd,iLr1,esiooemN0aAuvt-(laa.mit1DanHhnt9ii.lo.hy7DEnyMuC8iaddo)bo,lruiynocaBEMnxia.unpyAetecAi-osyro9trnyxatnn.,ali1bnndhro0onqeyAd---f, burn range We have also ft jnd that phytoene, a Health. National Cancer Inst 841.005 precursor pigment having abs irption maxima in the sunburn range, significantly deareased the andhaaat reaction m guinea pigs exposes IB Ihis isdlattan- In B PO addition, we ana others have shown that carotenoid EPtOCMtOLOQY OF BRAIN TUMORS pigments can inhibit the formation ol tree redketa F.H, Hoetitarg, Massachusetts General HospitaiT which have been implicated m photocarcinogeneaie. Neurology Service. 33 Fruit St. Boston. Maaaaehu- Therefore, we propose to study the effect of the aatta 02114 (R01 CA 22533-02) systemic administration of beta-carotene, phytoene. A case control study of 230 patients and 230 'best and otner carotenoid pigments on the development of skin tumors induced by sunburn radiation and topi cal carcinogens m hairless mica. Mend or ctaeett neighbor' controls is proposed to evaluate risk indicators of primary brain tumors (spe cifically Natotogiealfy-eonfWmed astrocytic tumors: We have establiaed dosage levels and routes of astrocytoma, glioma, gltoblaatama muMtarme, medul- administration which lead to significant accumuiaSon lobiaatome). DesprM the fact that brain tumors are ot beta-carotene andjxiytoen* m the akin of haataae th* primary source of cancer mortality m youth, that mica, with no apparent toxicity. Methode already a variety of bram tumor risk factors hav* bean sug- well-documented in the literature for the induction of geeted, and that experimental data exist linking brain skin tumors by sunburn radiation and topical carcino tumor development to speafle chemical carcinogens gen appkcation witt be used. Groups of haMoea mice and oneogante vkusea, no large pcpUatlon. con will be given carotenoids and appropriate ptaceboe, trolled study ha* bean done ta determine the risk and blood and skin levels of the pumenta wM be factor* of brain tumor. Through aalt-idminittarsd allowed to reach saturating levels before the tumor queattanneks and tetaphon* mtannew. we propose induction program begins. The tmee wM be ebearvad to: t. Detamwie th* raiattonatvp batween demo- tor ihe development ol skm change# and tumor*. taaphre charactentbca and risk of glial tumors. 2. Tumors will be studied histologically and graded. Evafuata th* rota of oceupaftanal and anvkonmantal Blood and skin carotenoid end vitamin A levels wet exposure* and risk. 3. Evaluate th* rota of trauma. 4 be measured. The results ol itabsticai anafyeae on Evafuata th* rota of fantaial factors. 5. Evaluate the the numbers ot tumors and the time ot tumor induc rol* Of infection ai a nsk factor. Although thta study tion in the various groups of mea wiN xidtcet# whoev is analytic in design, it i* hypothesis-generating in er the systemic administration of carotenoids has nature. The unique availability of a patient population any significant affect on tumor induction. which kiciuds* 100 new astrocytoma patients par SUPPORTED BY U.S. Dept, ot Health Education A welfare, Pubic Health Service, National Inet. of Health, National Cancer Inst. 831,446 year and th* aettv* bram tumor resesrch interests of th* ksvetEgatara have created situation m which a va8d study of the epidamtatogy of these tumors may be rnmpleted m an efficient and inexpensive 2.0222, BITUW OtOL EPOXIDE ANO OTHER DERIVATIVE* OF PAH ANO AZA-FAH R E. Lahr, University ot Oklahoma. Norman Campus, School of Arts A Sciences. Dept, ot Chemistry, M0 Pamngton Oval, Room 101. Norman, Oklahoma 73069 (R01 CA 22985-03) increasing evidence that dioi epoxides are important intermediates in the mutagenesis and carcinogenesis ot polycyclic aromatic hydrocarbons has bean amassed during the past year Quantum chemical calculations which we applied to estimate th* reac tivity ot dioi epoxides hav* proven successful m correctly predicting that bay region epoxides should b* the most reactive lor a given PAH. and hav* correct ly predicted the relative reactivity at dioi epoxides derived Irom different PAH. PAH nng-substituted with nitrogen (azs-PAH) are being inereeengfy recognized at significant environmental contaminant*, but hwm received meager attention from the standpoint of determining me metabolites involved in the cardno- genasa of th* compounds and thee structure-eclMty relationships. An examination of the Werttur* on benztOacndme derivatives suggests that dkk apox- ide and dihydrodtot intarmedtatas analogou* ta those SUPPORTED BY U.S. Dept of Health Education A Welfare, Public Health Servrc*. National inst. ot Health, National Cancer Inst 850,051 2.0224, BT BIOCHEMICAL STUDIES IN CHEMICAL CARCtNOGCNCSIS JA. UHtar, University of Wisconsin, Madison Campus, Medical School. Dept of Oncology. 307 N Chartaa St, Madison. Wisconsin 53706 (P01 CA 22484-02) Thta Program-Prolect encompasses a broad funda mental approach to th* chemistry, biochemistry, and biology of tumor initiation, promotion, and progres sion by chenVcata. Th* program include* major stud ies on th* activation of chemical carcinogen*, the interaction* of ultfmata carcinogen* with cellular macrotnotatules. biochemical events associated wtih the promotion of Mdatad cad* ta the development ol grows tumors, factors that affect th* dlNerwntiation ot cede and Me progression and regroealon of neoplas tic or praneoptasSc ceds, and th# bk>tagic*l and bio- chemical dlveriity of pranopfesdc and neoptaaoc le sion*. Th* program include* investigation! at th* 1-23 OL! 7170