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( ( :.. 16. Other sources of financial supportr ::> ~ .:ArT.'~~ : , • • . S. List financial support from all sources, Including own institution, for this Title of Project Mal.ignant Transformation of - •; DNA 'Inhibi,tors Cytogenetic Diagnosis and Etiology of Human Cancer ,Career Development Award to W.F..Be nedict. • `.• Fibr•inolysls, as a Parameter , - of In• Vit::ro 7rransformation . , ,; .. CURRENTLY ACTIVE Source (give grant numbers) Inclusive Amount Dates NCI - CA14226 145,701 2/1/73 - 1/31/76 NCI - CA15039 70,976 9/73 - 8/76 NCI - CA70996 125,000 6/1/75 - 5/31/79 NO1 - CP55641 46,818 first year) PENDING OR PLANNED Source Inclusive . (qive grant numbers) Amount Dates • ..~` . . . . Principal investigator Typ.d Name William F. Benedict, M.D. Signature .: . ,:~t.. . 1t• Is 'understood that the investigator and institutional officen in applying for a grant have read and accept the Council's "Statement of Policy Containing Conditions and Terms Under Which Project Grants Are Made." (213) 663-3341 2207 h T i ep one . Checks payable to Chi ldrens Hospi tal of _jped Name _ f{enrV B'. Ilunl~o _ Los Angeles .~.... __ ...-.~.c.- . . .... _ . . . .... ! ~T ( Mailing address for checks Chi ld f L H l i A and related research projects. Aree Cede Nvmber P.terute. Responsible officer of institution Tifie ++brtnn rens o osp ta os ngeles 3:pnan,re _ 4650 Sunset Blvd. Telephone .,., (213) 663-33++1 Los-Angeies, Caiffornfa 90027 50114491 [,n.w.. CTR /) l i 0438822

L.. : • Toxicity, Transformation,• and Chromosomal Aberrations as a Function of Aryl Hydrocarbon Hydroxylase Activity In Cell Cultures. r'i..-R. J. Cancer, 9:435-445, 1972. 50114492 3. 4. 5.' APPENDIX Biographical Sketch William F. Benedict, M.D. Biographical Sketch Peter A'. Jones, Ph.b. Biographical Sketch Walter E. Laug, M.D. Benedict, W.F., Rucker, N.; Faust, J., Kouri, R.E.: Malignant Transformation of Mouse Cells by Cigarette Smoke Condensate. Cancer Res., (in press)_-z -paper enclosed. Leug, W.E., Jones,• P.A., and* Benedict, 4/.F•: Studies on the*Relattonship Between,Fibrinolysis of Cultured Cells and Malignancy. J. Natl. Cancer Inst. Balance of Specific Chromosomes and•the Expression of Malignancy In Hamster ` ' Cells. J. Natl. Cancer Inst. (Jan. 1975). - paper enclosed. . . u •- G~:g,ar•ef>;g' ~ke~~6'rrdensatelEcacti,qns~ i~A~k; t19~55 , abi~r~ct enclo;ed. ',; ~ . . -.' . • . . . . . .. _ . : 8. Jones,,. P.A.l/and Benedict, W.F.: Chemothecapeutic Agents Cause Malignant :. V an,s.formatlori.' 'Cl inical Research; 1975 - abstract enclosed. 9.• •Benedict,, W.F.~,*Rucke'r, N., Mark, C., Kourl, R.: Correlation Between the . atcCanry, J'ti; Sp~ingarn, N.E., Kobori, J. and Ames, B.N.; The Detection of Carcin.ogens as Mutagens: Bacterial Tester Strains with R-factor Plasmids. (.Jar•r.: ,1j75) - paper enclosed. •Proc. Nat.'Acad. Sci., (In press - paper enclosed). `7 •• 'Ko i' R 'Wlittmtre C and Benedict W• inT~hootail4o q~Yit- Effd t" ~ . . • .,~ . • . . , , . . ~10.' Benedi'ct, W.F.i Early Changes in*Chromosomal Number and Structure after' Treatment'of'FeLal'Ramster Cultures witFi Tran•sforming Doses of Polycycli,c Hydrocarbons. J. Natl. Cancer Inst. 49:595-59D, 1972. il. Benedict, W.F., Gielen, J.E., Nebert, D.W.: Polycyclic Hydrocarbon-Produced I C/ R 1M/I I 04,3883

( > CURRICULUM VITAE ( 1 ;'PERSONAL INFORMATION: Name• B.usiness Address: Business Telephone: Home Address: H•ome Telephone: Da.te' of B i rth Placc.of Birth: .Ci`tizenship: Sex:' Mdrital Status: EDUCA.T.I ON: :..High School; year graduated: Col lege.o,'r Un;iversity': Medical School: l.nternshi'p:• ' Residencies: - _ • Fellowships:' ' Honors dnd, Awai•ds: ; , Licgnsure: William F. Benedict, M.D. Childrens Hospital of Los Angeles, r ! . ' 4650 Sunset Blvd., Los Angele's, Cal. 90027. Area code. (213) 663-3341, Extension 2207. 3537 Multiview Drive, Los Angeles, Cal: 874-1701. 1/21/42 I Middletown, U.S.A. Male New York ~ Single . f Middletown High School, 1960. Drew University, Madison, N.J., Zoology, 1964, Albany Medical Col•lege, Albany, N.Y,-M,D „ 1968. Childrens Hospital of Los Angeles, Pediatrics, 1969. Albany Medical College, Albany,'N.Y., Pediatrics, 1970. Oncology, 1972-1973, Childrens Hospital of Los Angeles. Career Development Award from the National Cancer Institute. California Board eligible - Pediatrics. ,, Board certl•fication: ' C. PROFESSiONAL BACKGROUND: Academic appoir,tments: Specific teaching •2 years, Childrens Hospital of Los Angeles, Department of Pediatrics, Hematology-oncology and Medical genetics, Assistant Professor. responsibilities: Specific administrative Military service: . D. SOCIETY MEMBERSHIPS: Local: Nationai: None American Association for Cancer Research; American Association for the Advancement of Science. 50114493 Tumor Clinic, Childrens Hospita.l of Los Angeles, Post-doctoral training. responsibilities: None Public Health Service, Lt. Commander, National Institute of Child Health and Development 'Bethesda, Maryland, 1970-1972. r C) I'1 ! l7 / 04,3884

L. William F. Benedict, M.D. Curriculum Vitae • . -2- E.. CONSULTANTSHIPS: None F.• RESEARCH ACTIVITIES: Research Interests: 1. Chemical Carcinogenesis. 2. Cytogenetics and Cancer. 3. Molecular Pharmacology of Chemotherapeutic Agents. Grants for reseamh: . 1. Career Development'Award - NC1, 7/74-6/7$. 2. Cytogenetic Diagnosis and Etiology of Human Cancer - NCI, 6/73-9/76. 3. Malignant Transformation of DNA Inhibitors - NCi, 2/73-2/.76 4. Relationshlp•Between Cell Transformation and Carcinogenesis, Tobacco Council of the•U.S., 7/73 - 3/74. 5. Endpoints for In Vitro Carcinogenesis Without Transplantation to Syngeneic ~ Hosts-NCI - 11/74-11/76. f i , 50114494 t CTR NN 04-3-685

BIBLIOGRAPHY Reviewed Journals • l..Porter, I.H., 3enedict, W.F., Drown, C.D. and Paul, B., Recent Advances in Molecular PatholoVy: A Review-Some Aspects of Chromosome Changes in Cancer, Exp. Mol. Path., II, 340-367, (,.969). 2. Benedict, W.F., Harris, N and Karon, 11.-, Kinetics of I-O-D-Arabinofuranosyl- cytosine-Induced Chromosome Dreaks, Cancer Res., 30, 2477-2483 (1970). 3. Denedict, W.F., 'orter•, Diagnosis of t•taI ignancy I,H., Drown, C.D. and Florcntin, R.A., Cytogenetic in Recurrent Meningioana, Lancet, 971-973 (1970). 4, Benedict, W.F.- and Karon, M., Chromatid O,reakagc: Cytosinc Arabinosidc- • Induced Lesions'by Ultraviolet Irradiati:on, Science, 171, 680-682 (1971). 1 5. Benedict, W.F „ Orown, C.D. and Porter, I,H „ Long Acrocontric Chromosomes in Malignant Effusions and Solid Tumors, New YorI~J. Hcd., 9, 9.52-955 (1971). 6. Benedict, W:F., Porter, I.N. and Brown, C.D.', The Cytogenetic Diagnosis of Malignancy .in Effusions, Acta Cvtol., 16, 3D4-3o6, (1972). , 7. Bchadict, W.F., uieIen, J.E and Nebert, D.W., Polycyclic-Hydrocarbon-produced Toxicity, Trans format ion, and Chromosomal Aberrations as a Function of Aryl Hydrocarbon Hydroxylase Activity in Cell Cultures, Int. J. Cancer, 9, 435-451, 1972. Benedict, W.F., Rapid Production of Numerical and Structural Abnorrnalities in Hamster Cells by Transforming Doses of Polycyclic Hydrocar•bons, J. PIatI. Canccr' Inst., 49, 585-590,'(1972). ._ . ... ::_~.__ • . -.~-:. .. , . Benedici:, IJ:F „ Nebart, D.W and•Thompson, E.D., Expression of i4ry1 Hydrocarbon Induction and Supprossion•of Tyrosine Aminotrarisfcragc: Induction in Somatic- cell Hybrids, Proc. Nat. Acad. Sci.. U.S.A.,69, 2179-2183, (1972) 10."Nebert, D.1J.,.Denedict, W.F., Gielen, J.E., Oesch, F. and Daly, J.W., Aryi Mydraca*rbon Flydroxylase, Epoxide Hydrase, and 7,i2-Oinmethylbenz (a) athracene- produced Skin Tumorigenesis in the House, HoI. Pharm;, 8, 374-379 (1972) ' ' 11. Karon, H. and DenecJict, W.F.,.Chroma.tid Breakage: Differential Effect of Inhib- itors of DNA Synthesis on G2. Scicncc, 178, 62, (1972). . 12. Ocnedict, W.F.,'Poul, 0 and Nebcrt, D•.W., Expression of Aryl Hydroxylase in Mousc-Hamster and Mouse-Man Hybrids, Diochcm. Dibnhys. Rcs. Conen.,.48, 293-298, (1972) 13. Oenedict, W.F., Considine, N., and.Nebert, D.W., Genctic Differences in Aryl Hydrocarbon Ilydrozylnsc Inrluctiori artd Dcnzo (a) pyrcnc-produccd Tumorigcnisis In The House, `tol. Pharm. 9: 266-277, 1973.. 14, Karon, M., Benedict, W.F and Rucker, N„ Mechanism of l-/-D-Arabinofurano-, sylcytosine Induced Cell Lethality, Cancer Res., 32, 2612-26)5, (1972). • ( 50114495 I r Cr f R Hf-'i 043886

15. • 16. ?aul 'o., Benedict, W.F., and Porter, I,H „ Giemsa Banding In An Established Line of a Human Malignant Meningioma, Humanoenetik 18:185-187, 1973. Benedict, IJ.F.,•Gielen, J.E., Owens, I.S „ Niwa, A., and Nebert, D.W., Aryl Hydrocarbon Hydroxylase Induction in Mammalian Liver Cell Culture-IV. Stimulation of the Enzyme Activity in Established Cell Lines Derived from Normai Rat Liver, Biochemical Pharm. 22:2766-2769, 1973. 17. Thompson, E.B., Benedict, W.F., Owens, i. and Nebert, D.W., Aryl Hydrocarbon Hydroxylase and Tyrosine Aminotransferase Activities in•Somatic Hybrids Derived From Hepatoma Tissue Culture._(Rat),Cells and 3T3 (Mouse) Benzo(a)pyrene Resistant Cells, Biochem. Biophvs. Res. Comm. 56:605-610, 197y ' ~• 18. Benedict, W.F., Rucker, N., Yaron, M., Ara-C Induced Chromatid Breakage: Effect of Inhibition"of DNA Synthesis, J. Natl. Cancer Inst. (Feb, 1975.) 19, i3enedict, W.F., Rucker, N., Mark, C.,.Kouri, R., Correlation Between the Balance of Specific Chromosomes and the Expression of Malignancy in Hamster Cel ls, J. Natl. Cancer Inst. (Ja.n, 1975) .. 20. Laug, W.E., Jones, P.A., and Benedict, W.F.,. Studies on the Relationship Between Fibrinolysis of cultured Cells and Malignancy, J. Natl. Cancer Inst. (Jan. 1975). . - 21. Benedict, W.F., Rucker, N., Faust, J., Kouri, R.E., Malignant Transformation -of Mouse Cells by Ciagrette.Smoke Condensate, Cancer Res. (iri-p~ess). i r f 4% 2. Kouri. R.E.; Kurtz, S.A., Price, P.J.-and Benedict, W.F „ Studies on ara-C- induced Malignant Transformat.ion of Hamster and Rat Cells in Culture,. Cancer Res. (submitted). , ! i 23. Kouri, R.E., Kurtz, S.A., Klement, V., Nicolson, M. and•Benedict, W.F., Stuc'ies on a Novel Type-C RNA Virus.Derived from Cultured Transformed Hamster . ; Cells, J.-Virolonv (submitted). . • . , t ,v • 50114496 i I CTR NN 04368"f-1`4

Cf R f fN 043888

c l ( THE Covxca. Fox ToBACCO RESEdxcs-U.S. TXc.- NEW:oRS. N. T. 20022 1976 (212) 421•838a ~ JAN 7 - t~ 11~1 ~ Application For Renewal of Ressoreh Grant ,,,> uar ~.: ...+ ~~ (Use extra pages as needed) First Renewal E] Second Renewal 0 Date: 12/15/75 TREET 110 ELaT 59rst 2 1. Principal Investigator (give title and degrees): 2. Institution d& address: William F' . Benedict, M15. * • Assistant Professor of Pediatrics University of Southern California Childrens Hospital of Los Angeles 4650 Sunset Blvd. ' Los Angeles, California 90027 3. Department(s) where research will be done or collaboration provided: •4. Short title of study: . . S. Proposed renewal date: Division of Hematology-Oncology and Medical Genetics Childrens Hospital of Los Angeles Malignant Transformation, Mutagenesis and FibrinDlysin Production of Cigarette Sinoke Condensate Fractions. June 1, 1976 6. How results to date have changed earlier specific research aims: Our Specific Aims have not changed. 7. How results to date have changed earlier working hypothesis: Our Specific Aims have not changed 50114464 ~ Cf f`-se f fN 0`'f'38891

. 2. 8. Any additional fadlities now required? Describe briefly, No 9. Any changes in personnel4 Append biographical sketches of new key professional pentionnelr Peter Jones, Ph.D. • 2096 effort (Delete) Nataraian Venkatesan, Ph.D. 20% effort (Add) l a 10. Append outline of experimental protocol for ensuing year. 11. List publications or papers in press resulting from this or closely related work. (append reprints or manuscripts not previously sent). 12.•Summory progress report (append In standard form as separate document, unleu recently submitted). 50114465 I CTR HN 04'3890

( .r 3. ( t ( Sub-Total for C 8,500 1,300 Runninp Total of A+ B+ C $40,274 Travel: To consult with Dr. Richard Kouri, Microbiological Associates, Bethesda, Md on this project and one meeting for Project Director (11000) Publication Costs: (300) Serum and Mdium Tissue Culture Dishes & Pipettes Radioactive Compounds Antilymphocyte Serum Animals & Care 3,500 2,500 700 800 11000 Sub-Tolal for B C. Other expenses (itemize) ' D. Permanent equipment (itemize) Incubator even if no salary requested) ': 13. Budget for the coming years A. Salaries (yive names or state "to be reeruited") Professional (give % time of investiQator(s) BENEDICT, William F. , M.D. LAUG,Walter, M.D. VENKATESAN, Natarajan ~ . . .~"Caiol': •..•. ' S. , B. •Consumable supplies (by major.mtepories) E. Indirect costs (15% of A+B+C) 50114466 % time Amount 15 .•15- - .•-• . • .. 20 $ 6,196 "4,272' 4,048 ._. -50 _ _ _ .. 9,628 Sub-Total for A $30,474 Sub-Totol for D E Total request 1,400 6 040 $47,714 CTR HN 043891