Grant Application - Environmental and Genetic Factors in Neoplasia

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Bio 1ogy Dcpa rtmen t Brookhaven S at ional Laboratory Brookhaven National Laboratory Upton, New York 11973 Health Sciences Center State University of New York Stony Brook, New York 11790

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CU ILl CArl ON PUBLIC HEALTH SERVICE TlIc progiram is t o bc untl crt ; i kc ti jointly by tlic Iliology and Eleclicnl Ocpartiilcnts of , wc propasc to train postdoctorals tut i cnt s, Erom a multi tud c of disc ip lincs,with three goals in mind. .facets involvcd i n cvcn simple problems of car cino gc nc s is, and 3) ah appreciation of the types. of research and information needed t o make quantitative es tim at cs of the risks o f proposal have a documented history of productivity in studies on the somatic and g cnet ic effects of environmental agents on living systems and on the roles of different genetic. backgrounds in determining the responses of such systems t o environmental agents. (1) will be approached by research experience and contact in the laboratory of one ofthe mentors (Pathology, Cell Biology, Genetics, Biochemistry, Biophysics, Radiobiology) working on problems such as respiratory carcinogen es is,coca rc in og cns, DNA and repair and recombination and errors in repair, normal and abnormal DNA synthesis, chromosomal RHA synthesis and,processing of RKA and radiation carcinogen es is. will be approached by participation of trainees and staff in joint weekly seminars and discussion groups a t Stony Brook and / o r Brookhaven. collaboration with trainees and staff of a proposed training grant in viral oncology submitte d by SUhT-SB. The two proposed training programs intend to organize,inthe summer of 1976, an intensive conference on Biology of Cancer: the role of genetics and en v iron - mental factors in the causes and control of neo pl asia. o f competence in a particular field such a s Pathology, Pharmacology, Toxicology, Genetics, Cell Biology, Biochemistry o r Biophysics a s demonstrated by productivity and references. Potential trainees will be obtained by inquiries to sponsors and 'by solicitation by public appointed in that order.Usually na sponsor may have more than one trainee and a reasonable distribution of trainees among the collaborating departments will be maintained. Support i s plans of trainees will be in the directions of research and training in public and private academic research laboratories concerned with carcinogen es is and environmental toxicology. 1. .BNL Biology Department: the main building contains approximately 86,000 sq. ft.with an additional 10,000 of grccnlrouse spocc a ccc s sib lc from the' main building. The dcpartment has a full timc paid staff of approxirnatcly 25in vc st ign tors. 2. BNL Medical Dcpartmcnt: tlicrc is a hospital,rcs cnr ch laboratory wing and mcdical rcs c arch reactor in one miin building, and additional veterinary scrvicc fac ili tics in two ncnrby small buildings. o f SIINY-Sn. The rcscnrcli laboratory s cc tion of the blcdical Dcpartnicnt proviclcs an arca o f hiv ct s it y South C;impiis total in go vcr 300,000 sq. ft. i n firpa. 'Tlicsc~pcrniancnt struct urc s We will attempt to giv c tli cm 1) in-dcpth knowlcdgc inot ~ cf icl dallied to. The scientists of the organizations cooperating in this These meetings will be held in The program proposed here will be administered by an Executive Committee listed on the BNL is designated as the sponsoring institution for purposes of financial --- They must have a high level They will be ranked by the Executive Committee in order of merit and level 1, and 1at a higher level.Future career "he hospital tins a capacity of 48 bctls and is n clinical campus

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the circulation of pertinent records arid documents as soci ; 1with the grant and the anticipated course on cancer. SUBIOIALS of TUINEE LXPEHSLS TOTAL FOR ENTIRE PROPOSED Consultants - Throughout the ;,:ar visits by 3to4consultants are anticipated. visits serve two purposes : fisst, they provide trainee exposure to some of the out - standings cie nr is ts in the Eicld of cancer and second, they are a source of evaluation and advise to the cx c cut iv c committce, sponsors, and trainees themsclvcs. to give a lcc t utc or s cm in nr. Each consultant is cxpectcd Thc costs ref lcc t an average for t rav cl Crom either None None None Nonc Supply costs initially arc $2,000 per trn in cc and atthc 3rd year an in crc as c of 5% Not all tr ii in ccs wil1 sliiirc cqir:iI cxpcricilcc a t ttmc of entry into tlla proxram. I n the. first ycnr 4to5 trn1ucc.s will be carried ovcr Erom tlw cur rc rl t training

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Yi. I Continua t y--, Pago $200 transportation cost to BNL for train cc upon nppointmctlt t o progr3m.

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W - carcinogen es is, DNA repair Res ea rch and Development Adminis t ra tion 1974 Senior Biophysicist, Brookhaven National Laboratory. 1967-1974 Professor of Biomedical Sciences,University of Tennessee1972-1973 Director, The University o € Tennessee, Oak Ridge Graduate School of Biomedical Biophysicist, Oak Ridge National Laboratory Scientific Director, Biophysics and Cell Physiology 1954-1961 Associate Professor,Physics and Biophysics, Yale University Dirtkcor of Graduate Studies in Biophysics Director o f Undcrgraduate Studies in Physics, which has activity toward ul tro viol ct - ir rod i a tcdd c oxy rib on ucl c ic acid : its action on transform in kdc oxy rib on ucl c ic acid. J. B act c riol. 102: 187-192 (1970). i n human cells : As cns i ' tivc assay utilizing tlic photolysis of bromodcoxyuridinc. PrOc. Natl. Acod. Sci, 58: 708-712 (1971). induced lesions in tltc DNA o f xcroclcrm? pigmentosum ccI1s. Biophysics ntid liiocnginccr. .I-:,293-346 (1972). Uiocitcm. Ilinpllys. Reg.

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and joining i n normit Iiumm and xercdcrma pfKmentosum cells aft c rut tra violet S tcp s in DNA chain elongation and DNA i n segments of normal size at long times after ultraviolet irradiation Of hum n cells. Biophys. J. 13: 1265-1275 (1973). Biophys. Res. Comm. 2:858-864 (1974). DNA rcp air in humn Nature New Biol. 240: 114-116 (1972)--. - Set low, R. B. The wavetengths in sunlight effective in producing skin cancer: damaged by chemical carcinogens and mutagens. genetic deficiency : overview. In: No le cula r lfechanisms for Repair of DNA, Set low, 8. B., and R. W. Hart. Direct evidence that damaged DNA results in neoplastic transformation - - a fish story. Proc. 5thInt. Congr. Rad. Res. (1974), in press. DNA repair in human p roger oid cells. Biochem. - . .. Ar he or et ical analysis. Proc. Natl. Acad. Sci. 3: 3363-3366 (1974). - -. Photo therapy in the newborn. Natl. Acad. Sci. Report, Div. bled. Sci. (1974) pp, 41. %bo forms of repair in the DNA of human cells We study the effects of physical and chemical carcinogenic agents on eu car yo tic (human, hamster, mouse) and proca ryo tic cells and on clones of fish. We pay particular attention to the damage induced i n DNA and its repair. The three known repair systems - 1) enzymic photo reactivation(specific for pyr imi dine dimer s), 2) excision repair(pre replication repair), and 3) post replication repair - are analyzed for their biological effects and their effects on DNA by a number o f techniques(direct determination of chemical products in DNA, unscheduled DNA sucrose gradient cent ri fuga tion, and gel electrophoresis). and the known genetic defects of the cells in attempting quantitatively to correlate damage t o DNA and neo plastic transformation. We use these observations, Ultraviolet radiation is a convenient model, injurious agent because: I) i t gives rise to. skin cancer ; 2) i t is subject to precise dos ime try ; 3) one of- the primary damages arising from irradiation is pyr imi dine dimers i n DNA, and this damage is well known and easily quantified in small amounts; and 4) a great deal i s known about the biological effects o f uv damage i n vlLruses, bacteria and i n many eu car yo tic systems. the only)environmentally produced changes i n DNA that havc been shown t o have biological conscqucnces -- killing,mutation and n co plastic transformation, Pyr imi dine dimer s in DNA arc one of the few (if not

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1968- Medical Department, Brookhaven National Laboratory 1970- Professor of Pathology, SUNY, Stony Brook Shcllsbarger, C.J., and others. ~,12-Diuic~liylbcnz3iItliraccnc-Illduccd Elnmniary Ncoplas in in Rats. A.ffirmative Action Representative; Head, Radiobiology Division Director, USPHS post-Doctoral Training Grant Professor of Zoology, Coordinator of Kresge Radioisotope Laboratory, University Chairman, Interdepartmental Graduate Rad iat ion Biology Program. Cliairmaa, Animal Care Committee, Medical School Ncmboy, Scientific Review Committee, American Cancer Society. Mammary Neoplasia in Sprague-Dawlcy or Long-Evans Rat: Rat Wunmary Carcinogenesis Following Ncutron or X-Radiatit Effects of Neonatally hdminiscercd Scx Steroids on civcil Singly or Combined on Itat &fanuiiary Carcinogcncsis. J. Not 1. Canccr I n s t

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PRIVACY ACT MATERIAL REMOVED The objcctivc is to study basic mccliclnisms of radiation carcinogcncsis using primarily tlic rclntivcly largc and rclativcly rapid milnniiary ncoplasric , rcsponsc of tlic fcmalc rat to ionizing radiation. T h i s particular modcl has becn clioscn for studics of radiatioecarcinogcnosis bccausc a largc body of data conccrncd with the neoplastic response of rat inammary tissuc lias bcen accumuli~tcd, the model system lcnds itsclf to meaningful cxpcrimcntation and the animal model appears to be reasonably close to the human situation. general, young, fcmale rats are exposed to a single sub-leclial dose of x-radt- - ation and the development of mammary neoplasia is followcd for a one-year obtained by experimental radiations, radiation with chenical carcinogens, radiation after hormonal modifications, radiation of different strains of rats and radiation with certain environmental contaminants. Experimental radiations-- include: fractionation and protraction; various dose rates; and various qualities of linear energy transfer (LET). These data serve then as a base-line for the comparisons with data

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1 OEGREE ICON FERRE DI University of Nic hig an, Ann Arbor, Mi. %.A. MOD.U n ivers it y of Michigan, Ann Arbor, Mi. 1969-70 Professor and Chairman, Department of ? a th ology, Health Sciences Center, 1954-69 Chief, Pathology-Physiology Section, Biology Div. Oak Ridge Natl. Lab. 1951-54 Instructor in Pathology,University of Michigan 1948-50 Resident in Pathology,University of Michigan Prof,of Pathology, and Dean, School of Basic Health Sciences,State University of New York at Stony Brook Attending Pathologist, Medical Dept., Brookhaven National Lab. , Upton, N. Y. State university of New York a t Stony Brook Intern.University Hospital, Ann Arbor, Michigan Transitory, as compnrcd with Pcrmancnt, Iligh - h lt it u dc Exposurc on tllc Pnthogcncsis of s pont an co us and X-ray 'intlUCud Neoplasms i n RF/Un Mice. Executive Committee Member and