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CHARLES HEIDELBERGER December23, 1920-January 18, 1983 ELIZABETH C. MILLER AND JAMES A. MILLER CHARLES HEIDELBERGER was a scientist with broad tal- ents. Trained as an organic chemist, he later became a skilled biochemist ant! cell culturist. From his many years of research on cancer chemotherapeutic agents, he also devel- opecl an impressive knowledge of human cancer and its treat- ment. He was a prolific reader, an original thinker, a synthe- sizer of Pleas, an avid explorer of new concepts, and a lucid writer. Using these talents and his fine intellect, Charles Hei- delberger macle his mark in science by seminal ant! extensive contributions to three areas of cancer research. He pioneered in the use of 3H- and i4C-labeled carcinogenic polycyclic hy- cirocarbons in the study of their metabolism and their inter- actions with target tissues. He was an early investigator of the development of systems for the malignant transformation by chemicals of mammalian cells in culture, and with his col- leagues he clevelope(1 one of the most widely used systems for the transformation of mouse fibroblasts. His most impor- tant accomplishment, however, was the design, synthesis, pre- clinical testing, and analysis of the mechanisms of action of 5-fluorouracil (5-FU) and related compounds for the chemo- therapy of cancer. 259

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260 BIOGRAPHICAL MEMOIRS EARLY YEARS This remarkable scientist was born on December 23, 1920, the only child of Michael and Nina knee Tachau) Hei- clelberger. Known as Charlie to his many friends, Heidelber- ger was most fortunate to be brought up in a warm and lov- ing family that included the arts and sciences among its many interests. In adclition to his parents, his immediate family in New York City incluclec! his mother's mother anct five of his mother's sisters. Charlie's grandmother was much beloved by the whole family. She ant! her daughters, Charlie's aunts, maintained close relations with the Heidelbergers. Both Nina and Michael Heiclelberger had a talent for and interest in music, and they made their home a center for its enjoyment. At the time of Charlie's birth, Michael Heidelberger was al- ready establishecl at the Rockefeller Institute for Meclical Re- search as a promising young organic chemist. Thus, from his earliest years, Charlie came to know scientists, both from the Uniter! States and Europe, ant! to hear discussions of their work. In an account written cluring his last year of high school Charlie listecl Drs. O. Avery, R. Loeb, and W. Oster- hout all of the Rockefeller Institute among his friends. In addition, as a child, Charlie accompanies! his parents on several trips to Europe, through which he gained an early appreciation of the international nature of science anc! of culture. Except for summer vacations, Charlie lived in New York City from his birth until he gracluated from high school. He attended the Birch-Wathen School, a private school at 94th Street. According to Charlie's account, he passed his early years in a mi(lcile- to upper-cIass school that emphasized learning the funciamentals of science, history, and language. His extracurricular activities in high school incluclecl music, drama, and journalism. At about the age of six, Charlie was

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CHARLES HEIDELBERGER . 261 given a quarter-size violin and a few violin lessons by Toscha Seiclel, an eminent musician and family friend, who later pre- sented him with his first full-size violin. From the age of nine, Charlie spent many of his summers at a boys' camp on Cape Coil, first as a camper and later as a junior counselor. At camp he developed a fanciness for and great competence in sailing, which he was to enjoy as an avo- cation in college, cluring his twenty-eight years in Madison, Wisconsin, and after moving to Los Angeles. In 1937 Heidelberger was admitted to Harvard College, where he majored in chemistry. On completing the B.S. de- gree in 1942, he began his graduate work at Harvard, earn- ing M.S. and Ph.D. degrees in organic chemistry in 1944 and 1946, respectively. His Ph.D. advisor was the eminent organic chemist Louis Fieser, who was then carrying out research on several war-relatecl projects. Accordingly, the second part of Heiclelberger's thesis, "The Synthesis and Antimalarial Activ- ity of Some Naphthoquinones," came out of the war effort of Fieser's group. The results of his thesis were published, to- gether with those of his colleagues, in a series of multi- authored papers in the journal of the American Chemical Society. The summer following completion of his Ph.D. degree, Hei- delberger was appointed an instructor in chemistry at Har- varcI, ant! he gave the summer lectures in organic chemistry while Fieser was on sabbatical leave. Although Fieser had set aside his research on the carcinogenic polycyclic aromatic hy- (lrocarbons during the war years, the laboratory at Harvard introclucect Heidelberger to these carcinogens, which became central to his later research. His graduate work also intro- duced him to chemotherapeutics, his second principal area of research. For postcloctoral work, Heiclelberger mover! to the Don- ner Laboratory of the University of California, Berkeley, where he joined Melvin Calvin and his associates in the study

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262 BIOGRAPHICAL MEMOIRS of carbon-14 as a too! for the eluciciation of metabolic reac- tions. During this two-year period, Hei(lelberger synthesized the first carbon-14-labeled carcinogen, dibenzanthracene- 9,10-carbon-14 (now known as E7,12-~4C]dibenz~a,h~anthra- cene) and carrier! out initial studies on its metabolism in the mouse. At the same time, working with S. Lepkovsky, he syn- thesizect ~4C-labelecl tryptophan and inclole-3-acetic acid for analysis of tryptophan metabolism. This perio(1 also saw Hei- delberger's preparation, with M. Calvin, J. C. Reid, B. M. Tol- bert, ant! P. F. Yankwich, of the textbook Isotopic Carbon. This book, published in 1949, was the stanciarct textbook for stu- dents using carbon 14 in metabolic studies for more than a decacle. RESEARCH CAREER Heiclelberger's studies on f~4C]clibenz~a,h~anthracene caught the attention of Harold P. Rusch, director of the then relatively new McArdIe Laboratory for Cancer Research at the University of Wisconsin. While attencling a meeting on the West Coast, Rusch visited Heiclelberger at the Donner Laboratory and persuaded him to accept a position as assist- ant professor of oncology at the McArdIe Laboratory. In 1948, Heiclelberger and his wife Juclith moved to Madison, marking the beginning of his productive twenty-eight years at McArdIe. Hei(lelberger was brought to the McArdle Laboratory to establish facilities for the use anct quantitation of carbon-14 for metabolic studies, to provide expertise in the synthesis of labeler! compounds (at a time when they were not commer- cially available), anti to pursue the problem of cancer accord- ing to his own Pleas. He carried out each of these activities with vigor. Heiclelberger soon set up a centralize(1 clepart- mental facility for the quantitation of carbon-14 (and later for tritium and P-321. He kept the facility operating with

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CHARLES HEIDELBERGER 263 state-of-the-art technique for nearly thirty years. With his ex- pertise in the use of carbon-14, he colIaboratec! on projects with most of the members of the McArdle staff cluring his first decade there. Together with Van R. Potter, Heidelberger initiated his research at the University of Wisconsin with a study to test A. G. Ogsten's theoretical deduction "that the asymmetric oc- currence of isotope in a product cannot be taken as conclu- sive evidence against its arising from a symmetrical precur- sor." ~ Heidelberger and Potter's study completely confirmed Ogston's theory that an asymmetric enzyme can (distinguish between identical groups of a symmetrical compound, dem- onstrating the asymmetrical synthesis of citric acid labellec3 with TIC. Potter's interest in exploring a possible metabolic pathway from citric acid cycle intermediates to pyrimidines using orotic acid and Heidelberger's expertise as an organic chemist made them well-suited for collaborative work. They accomplished the synthesis of Li4C]orotic acid with Potter's student R. HurIburt in 1950. Heidelberger's later studies of nucleic acid pyrimidines were built on this experience. CARCINOGENIC POLYCYCLIC AROMATIC HYDROCARBONS Heidelberger's synthesis of [l4C]dibenz(a,h)anthracene gave him the opportunity to examine the metabolism of this hydrocarbon in much greater cletai! than had been possible with the spectroscopic methods of earlier workers, and he identified several degradation products. In the late 1940s and early 1950s, when there was great interest in protein- bound carcinogens in target tissues, Heiclelberger and his students used labeled hydrocarbons to determine their co- valent binding to mouse-skin protein and, especially, to quan- ' A. G. Ogston, "Interpretation of experiments on metabolic processes using iso- topic tracer elements," Nature (London), 162(1948):963.

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264 BIOGRAPHICAL MEMOIRS titate the relative levels of binding of several hydrocarbons in relation to their carcinogenic activities. Furthermore, they studied in depth the specificity of binding of the hydrocar- bons to various soluble mouse-skin proteins as a function of - t near carcinogenic activities. After K. E. Wi~zbach (Argonne National Laboratory) re- ported his general method for the tritiation of organic com- pounds,2 Heidelberger prepared tritiated polycyclic aromatic hydrocarbons. The much higher specific activities of the tri- tiated hydrocarbons facilitated in viva approaches to macro- molecular binding of the hydrocarbons. With G. R. Daven- port, Heidelberger was the first to report the covalent binding of a carcinogenic polycyclic hydrocarbon to mouse- skin DNA and RNA. But because of technical problems re- lated to the determination of tritium in cesium chloride so- lutions in the Heidelberger laboratory, the first definitive report on the covalent binding of polycyclic aromatic hydro- carbons to DNA of target tissues was that of P. D. Lawley and P. Brookes (Chester Beatty Research Institute, London). Using tritiated dibenz~a,h~anthracene, Heidelberger and his colleagues later made one of the first observations of the mi- crosomal metabolism of a polycyclic aromatic hydrocarbon to . an epoxlue. The studies on the polycyclic aromatic hydrocarbons were later melded with Heidelberger's work on oncogenic trans- formation in cell culture. In these investigations, Heidelber- ger and his colleagues studied the possible relationship between the formation of K-region epoxides of the hyciro- carbons and their mutagenic and transforming activities. As this work was being published, the complexity of the meta- bolic activation of the polycyclic aromatic hydrocarbons and 2 K. E. Wilzbach, "Tritium-labeling by exposure of organic compounds to tritium gas," [. Amer. Chem. Soc., 79(1957): 1013.

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CHARLES HEIDELBERGER 265 the involvement of other sites on the molecules were becom- ing evident from the reports of P. Sims, P. Grover, and their colleagues at the Chester Beatty Research Institute.3 Heidel- berger ant] his colleagues continued to probe this area, but other research interests took the lead. TRANSFORMATION OF CELLS IN CULTURE As Heiclelberger carrier} out his early stucties on carcino- gen metabolism in relation to carcinogenesis, he was im- pressed with the limitations imposed by whole-animal sys- tems on the elucidation of the carcinogenic process. He began, accorclingly, to search for other systems. lIse Lasnitzki tract recently shown that organ cultures of mouse prostate glancis treated with the carcinogen 3-methylcholanthrene de- veloped an atypical morphology somewhat resembling that observed in tumors. In 1962 Heiclelberger took a seven- r~onth sabbatical to work with Lasnitzki at the Strangeways Laboratory in Cambridge, England, to learn the techniques required for the clevelopment of an organ culture system anti to develop a background in the cellular aspects of biology. On returning to the McArdle Laboratory, Heidelberger treated organ cultures of mouse prostate with polycyclic aro- matic hydrocarbons, looking for neoplastic properties in the cultures. This laborious work, carried out on a rather large scale, yieldecl morphologically observable cytopathology but no tumors on transplantation of the cultured cells into isol- ogous mice. In studies with P. T. Type, however, the hyciro- carbon-treated cultures eventually yielded permanent lines of cells that gave rise to transplantable tumors. This success encouraged Heidelberger and his colleagues to culture C3H mouse-prostate cells for the selection of non- 3 D. H. Phillips and P. Sims, "Polycyclic aromatic hydrocarbon metabolites: their reactions with nucleic acids," in Chemical Carcinogens and DNA, P. L. Grover, ea., vol. 2 (Boca Raton, Florida: CRC Press, 1979), pp. 29-57.

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266 BIOGRAPHICAL MEMOIRS malignant cell lines that conic! be treated with carcinogens in a controllec! manner. Such cell lines, which were aneuploict, were obtained, but ceased to grow on reaching confluence. Nor did they produce tumors on inoculation into irradiatecl isologous mice. But treatment of the rapidly growing cells with 3-methy~cholanthrene caused some of them to continue growing after reaching confluence that procluced fibrosar- comas on injection into irradiatect mice of the same strain. Although malignant transformation of cultured roclent cells by chemicals was achieved somewhat earlier by other inves- tigators, Heidelberger and his colleagues were the first to obtain a system depenclent on an established line of cells. Later, Heiclelberger with C. Reznikoff anc! J. Bertram es- tablished the C3H/IOTI/2 cell-line that became a standard too! for studies of mammalian cell transformation anc! mu- tagenicity. Heidelberger and his associates showed that there was a general quantitative relationship between the in viva carcinogenic activities of polycyclic aromatic hydrocarbons ant! their abilities to cause malignant transformation of these cultures! cells. As noted above, they also explored the reac- tivity of the hydrocarbons with cellular macromolecules in relation to malignant transformation and mutagenesis in cul- ture. Heidelberger and his colleagues attacked other, more bio- logical, problems with regard to the nature of malignant transformation. These inclucled early explorations of pos- sible retroviral involvement in transformation by chemicals and of stochastic aspects of transformation. They showed that carcinogenic chemicals inclucec3 alterations in cells that caused them to become malignant, as opposer! to a situation in which the carcinogen facilitated the selection of preexist- ing malignant cells. They further showed that (as others had clemonstratec] earlier for malignant transformation in whole animals) each cell line transformer] in culture hac! unique

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CHARLES HEIDELBERGER 267 antigenic properties that clid not cross-react with those of other inclepenclently transformed cells. CANCER CHEMOTHERAPY Heidelberger's intellect and energies were such that, from his earliest days at the McArc3le Laboratory, he routinely car- ried out two quite separate research programs in parallel. Starting in the early 1950s, he turned his interest in the bio- synthesis of nucleic acids in normal and tumor tissues and- from his graduate student daysin chemotherapy toward a search for pyrimiclines that would be therapeutic for cancer. Following a 1954 report by R. I. Rutman, A. Cantarow, and K. E. Paschkis ~ Jefferson Medical College) on the greater ex- tent of incorporation of uraci! into rat liver tumor DNA than into normal liver DNA,4 Heiclelberger made similar obser- vations on a variety of tumors and their normal tissues of origin. On the basis of the exceptional toxicity of fluoroacetic acid through its metabolism to fluorocitric acid and our stucI- ies on fluorinated carcinogens, Heiclelberger reasoned that substitution of a fluorine atom into the 5-position of uracil might prevent its metabolism to thymidylic acid and thus in- terfere with DNA synthesis. He thus embarked on the syn- thesis of 5-fluorouracil. Following his first stucties, which shower! that 5-flu- orouraci! inhibited the growth of a series of transplanted ro- dent tumors, Heiclelberger enlisted the cooperation of Rob- ert Duschinsky at Hoffman-LaRoche to perfect the synthesis of 5-fluorouraci! so that tests on its therapeutic effects for tumors conic! be expanded. Clinical trials, first carried out at the University of Wisconsin by A. R. Curreri and F. Ansfielcl at Heidelberger's urging ancl with his cooperation, clemon- 4 R. J. Rutman, A. Cantarow, and K. E. Paschkis, `'Studies in 2-acetylamino flu- orene carcinogenesis. III. The utilization of uracil-2-C'4 by preneoplastic rat liver and rat hepatoma," Cancer Res., 14(1954):1 19-123.

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268 BIOGRAPHICAL MEMOIRS strafed that the new drug hac! clinical promise. Further stud- ies by a number of clinical investigators have given 5- fluorouraci! an important place in the chemotherapeutic treatment of several human malignancies, especially cancer of the female breast and of the colon. In acIdition to 5-fluorouracil, Heiclelberger's interest in fluorinated pyrimidines lect to the syntheses in his laboratory of 5-fluorodeoxyuridine (which has received limited use in cancer chemotherapy), 5-fluorocytosine (clinically effective against yeast and fungal infections), and 5-trifluoro- methyIdeoxyuriclylic acid (a tumor inhibitor that is also very active against some DNA virus infections for example, vac- cinia virus and herpes simplex, when applied locally). Over a span of about twenty years, Heidelberger's labo- ratory contributed greatly to our understanding of the bio- chemical mechanisms of action of 5-fluorouraci! anc! relater! compounds. Heidelberger observed that 5-fluorouraci! is in- corporated into RNA in place of uracil. However, probably the more important biological effect of 5-fluorouracil in re- lation to inhibition of tumor growth appears to be the pow- erful inhibitory activity of its metabolite 5-fluorodeoxyuri- clylic acid for thymidylate synthetase. He examined the mechanism of action of thymidylate synthetase and of its in- hibition by 5-fluorocleoxyuridylic acic! in a number of papers. Finally, one of his last scientific achievements was to clevelop sensitive assays for this enzyme, its normal substrate (leox- yuriclylic acid, and 5-fluorodeoxyuridylic acic! in tumor biop- sies, so that these could be studied in relation to the thera- peutic responses of individual tumors to 5-fluorouracil. These contributions to cancer chemotherapy earned Hei- clelberger much well-cleservecl recognition. His scientific de- cluction that 5-fluorouraci! might be chemotherapeutic for cancer, his development of this idea from chemical synthesis through preclinical testing, his collaboration in the first clin-

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CHARLES HEIDELBERGER 293 With I. S. Bertram. Cell-cycle variations in oncogenic transforma- tion in synchronized mouse embryo cells in culture. In: The Cell Cycle and Malignancy, pp. 359-68. Oak Ridge, Tenn.: U.S. En- ergy Research and Development Administration. With N. G. Kundu, I. A. Wright, K. L. Perlman, and W. Hallett. Cyclopentafflisoquinoline derivatives designed to bind specifi- cally to native deoxyribonucleic acid. 1. Synthesis of 3-ethoxy- 8-methyl-7~5)H-cyclopentaLfJisoquinoline. I. Med. Chem., 18: 395-99. With N. G. Kundu and W. Hallett. CyclopentaLf~isoquinoline de- rivatives designed to bind specifically to native deoxyribonucleic acid. 2. Synthesis of 6-carbamylmethyl-8-methyl-7~5)H-cyclo- pentatf~isoquinolin-3~2H)-one and its interaction with deoxyri- bonucleic acid and poly~deoxyribonucleotides). J. Med. Chem., 18:399-403. With U. R. Rapp, R. C. Nowinski, and C. A. Reznikoff. Endoge- nous oncornaviruses in chemically-induced transformation. 1. Transformation independent of virus production. Virology, 65:392-409. Fluorinated pyrimidines and their nucleosides. In: Antineoplastic and Immunosuppressive Agents, vol. 38/2, ed. A. C. Sartorelli and D. G. Johns, pp. 193-231. New York: Springer-Verlag. With A. R. Peterson and H. Peterson. Reversion of the 8- azaguanine resistant phenotype of variant Chinese hamster cells treated with alkylating agents and 5-bromo-2'-deoxyuri- dine. Mutat. Res., 29:127-37. Chemical carcinogenesis. Annul Rev. Biochem., 44:79-121. With M. I. Embleton. Neoantigens on chemically transformed cloned C3H mouse embryo cells. Cancer Res., 35:2049-55. With I. S. Bertram and A. R. Peterson. Chemical oncogenesis in cultured mouse embryo cells in relation to the cell cycle. In Vitro, 11 :97-106. On the molecular mechanism of the antiviral activity of trifluoro- thymidine. Ann. N.Y. Acad. Sci., 255:317-25. With S. Nesnow. A rapid and sensitive liquid chromatographic as- say for epoxide hydrase. Anal. Biochem., 67:525-30. With F. Bairstow. Increased thymidine uptake by methylcholan- threne-treated C3H/lOTl/2 cells. Int. J. Cancer, 16:370-75. With P. F. Boshell. Chemical oncogenesis in cultures. In: Recent Top- ics in Chemical Carcinogenesis. Gann Monogr., 17:39-58.

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294 BIOGRAPHICAL MEMOIRS Studies on the cellular mechanisms of chemical oncogenesis in cul- ture. In: Fundamental Aspects of Neoplasia, ed. A. A. Gottlieb, 0. J. Plescia, and D. H. L. Bishop, pp. 357-63. New York: Springer-Verlag. With S. Nesnow. Pyridine nucleosides related to 5-fluorocytosine. I. Heterocycl. Chem., 12:941-44. 1 1976 With P. A. tones, W. F. Benedict, M. S. Baker, S. Mondal, and U. Rapp. Oncogenic transformation of C3H/lOTl/2 clone 8 mouse embryo cells by halogenated pyrimidine nucleosides. Cancer Res.,36:101-7. Chemically and metabolically induced DNA adducts: Relationship to chemical carcinogenesis. In: Aging, Carcinogenes~s, and Radia- tion Biology. The Role of Nucleic Acid Addition Reactions, ed. K. C. Smith, pp. 341-71. New York: Plenum Press. With P. V. Danenberg. The effect of Raney nickel on the covalent thymidylate synthetase-5-fluoro-2'-deoxyuridylate-5, 10-meth- ylenetetrahydrofolate complex. Biochemistry, 15: 1331-37. With I. W. Keller. Polycyclic K-region arene oxides: Products and kinetics of solvolysis. I. Am. Chem. Soc., 98:2328-36. With T. L. Chwang, W. G. Wood, J. R. Parkhurst, S. Nesnow, and P. V. Danenberg. Synthesis and biological studies of 3-~-D- ribofuranosyl)-2, 3-dihydro-6H-1, 3-oxazine-2, 6-dione, a new pyrimidine nucleoside analog related to uridine. I. Med. Chem., 19:643-47. With B. K. Bhuyan and A. R. Peterson. Cytotoxicity, mutations, and DNA damage produced in Chinese hamster cells treated with streptozotocin, its analogs, and N-methyl-N'-nitro-N- nitrosoguanidine. Chem.-Biol. Interact., 13: 173 - 79. With I. R. Parkhurst and P. V. Danenberg. Growth inhibition of cells in culture and of vaccinia virus infected HeLa cells by de- rivatives of trifluorothymidine. Chemotherapy, 22:221-31. With J. R. Parkhurst. Rapid lysis of vaccinia virus on neutral su- crose gradients with release of intact DNA. Anal. Biochem., 71 :53-59. With S. Nesnow. The effect of modifiers of microsomal enzymes on chemical oncogenesis in cultures of C3H mouse cell lines. Can- cer Res., 36: 1801-8. With S. Mondal. Transformation of C3H/lOTl/2 C18 mouse em-

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CHARLES HEIDELBERGER 295 bryo fibroblasts by ultraviolet irradiation and a phorbol ester. Nature (London), 260:710-11. With S. Mondal and D. W. Brankow. Two-stage chemical oncoge- nesis in cultures of C3H/lOTl/2 cells. Cancer Res., 36:2254- 60. With A. M. Sarrif, P. V. Danenberg, and B. Ketterer. Separate iden- tities of ligandin and the in-protein, a major protein to which carcinogenic hydrocarbons are covalently bound. Biochem. Biophys. Res. Commun., 70:869-77. With I. F. Holland. Chemioterapia antineoplastica. (In Italian.) In: Enciclopedia del Novecento, vol. 1, pp. 746-69. Istituto dell' Enciclopedia Italiana. With A. M. Sarrif. On the interaction of chemical carcinogens with soluble proteins of target tissues and in cell culture. In: Gluta- thione: Metabolism and Function, ed. I. M. Arias and W. B. takoby, pp. 317-38. New York: Raven Press. With A. R. Peterson, D. F. Krahn, H. Peterson, B. K. Bhuyan, and L. H. Li. The influence of serum components on the growth and mutation of Chinese hamster cells in medium containing 8-azaguanine. Mutat. Res., 36:345-56. With l. W. Keller and N. G. Kundu. An unusual arene oxide re- action. Solvent capture during acid-catalyzed solvolysis of 7,1 2-dimethyl-benzEajanthracene 5,6-oxide. J. Org. Chem., 4 1 :3487-89. With J. W. Keller, F. A. Beland, and R. G. Harvey. Hydrolysis of syn and anti-benzoka~pyrene diol epoxides: Stereochemistry, kinet- ics, and the effect of an intramolecular hydrogen bond on the rate of syn diol epoxide solvolysis. ~. Am. Chem. Soc., 98:8276- 77. Studies on the mechanisms of carcinogenesis by polycyclic aromatic hydrocarbons and their derivatives. In: Carcinogenes~s. Vol. 1, Polynuclear Aromatic Hydrocarbons: Chem~stry, Metabol~sm, and Car- cinogenes~s, ed. R. I. Freudenthal and P. W. tones, pp. 1-8. New York: Raven Press. 1977 With D. F. Krahn. Liver homogenate-mediated mutagenesis in Chinese hamster V79 cells by polycyclic aromatic hydrocarbons and aflatoxins. Mutat. Res., 46:27-44. With S. Nesnow. The effects of microsomal enzymes on chemical

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296 BIOGRAPHICAL MEMOIRS oncogenesis in culture. In: Biological Reactive Intermediates, ed. D. J. Jollow, J. J. Kocsis, R. Snyder, and H. Vainio, pp. 455-67. New York: Plenum Press. Chemical carcinogenesis. Cancer, 40:430-33. With A. R. Peterson, S. Mondal, D. W. Brankow, and W. Thon. Ef- fects of promoters on DNA synthesis in C3H/lOTl/2 mouse fibroblasts. Cancer Res. 37:2323-27. Oncogenic transformation of rodent cell lines by chemical carcin- ogens. In: Origins of Human Cancer, ed. H. H. Hiatt, {. D. Wat- son, and I. A. Winsten, pp.1513-20. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory. 1978 With A. R. Kennedy, S. Mondal, and }. B. Little. Enhancement of x-ray transformation by 12-0-tetradecanoylphorbol- 13-acetate in a cloned line of C3H mouse embryo cells. Cancer Res., 38:439-43. Studies on the cellular mechanism of chemical oncogenesis. In: Integration and Excision of DNA Molecules, ed. P. H. Hofschneider and P. Starlinger, pp. 106-11. Berlin: Springer-Verlag. With A. M. Sarrif, K. L. McCarthy, and S. Nesnow. Separation of glutathione S-transferase activities in epoxides from the mouse liver in-protein, a major polycyclic hydrocarbon-binding pro- tein. Cancer Res., 38:1438-43. With S. Mondal and A. R. Peterson. Initiation and promotion in cell cultures. In: Carcinogenes~s. Vol. 2, Mechanisms of Tumor Pro- motion and Cocarcinogenes~s, ed. T. I. Slaga, A. Sivak, and R. K. Boutwell, pp. 197-202. New York: Raven Press. With S. Mondal and D. W. Brankow. Enhancement of oncogenesis in C3H/lOTl/2 mouse embryo cell cultures by saccharin. Science, 201: 1141-42. With A. R. Peterson, l. R. Landolph, and H. Peterson. Mutagenesis of Chinese hamster cells is facilitated by thymidine and deoxy- cytidine. Nature (London), 276:508-10. 1979 With A. R. Peterson and H. Peterson. Oncogenesis, mutagenesis, DNA damage, and cytotoxicity in cultured mammalian cells treated with alkylating agents. Cancer Res., 39:131-38. Oncogenic transformation of cell cultures by polycyclic aromatic

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CHARLES HEIDELBERGER 297 hydrocarbons and their derivatives. In: Polycyclic Hydrocarbons and Cancer, vol. 2, ed. H. V. Gelboin and P. O. P. Tsto, pp. 269- 77. New York: Academic Press. With I. Landolph. Chemical carcinogens produce mutations to ouabain resistance in transformable C3H/lOTl/2 C18 mouse fibroblasts. Proc. Natl. Acad. Sci. USA, 76:930-34. With S. Mondal. In vitro chemical carcinogenesis. In: Carcinogens: Identification and Mechanisms of Action, ed. A. C. Griffin and C. R. Shaw, pp. 83-92. New York: Raven Press. With R. G. Moran and C. P. Spears. Biochemical determinants of tumor sensitivity to 5-fluorouracil: Ultrasensitive methods for the determination of 5-fluoro-2'-deoxyuridylate, 2'-deoxyurid- ylate, and thymidylate synthetase. Proc. Natl. Acad. Sci. USA, 76: 1456-60. With R. G. Moran. Determinants of 5-fluorouracil sensitivity in hu- man tumors. Bull. Cancer (Paris), 66:79 - 83. With S. Mondal. Ultraviolet light in the oncogenic transformation of cultured C3H/lOTl/2 mouse embryo cells. Natl. Cancer Inst. Monogr., 50:71-73. With E. B. Gehly, W. E. Fahl, and C. R. {efcoate. The metabolism of benzota~pyrene by cytochrome P-450 in transformable and nontransformable C3H mouse fibroblasts. J. Biol. Chem., 254: 5041-48. With D. H. King. Trifluorothymidine. In: Antiviral Agents, ed. D. Shugar. Vol. 6, Pharmacological Therapies, pp. 427-42. Oxford: Pergamon Press. With R. G. Moran and M. Mulkins. Role of thymidylate synthetase activity in development of methotrexate cytotoxicity. Proc. Natl. Acad. Sci. USA, 76:5924-28. With }. R. Lillehaug and S. Mondal. Establishment of epithelial cell lines from adult mouse regenerating liver. In Vitro,15:910 - 16. 1980 With S. Mondal. Inhibition of induced differentiation of C3H/ 10T1/2 clone 8 mouse embryo cells by tumor promoters. Can- cer Res., 40:334-38. Assays for in vitro carcinogenesis, initiation, and promotion. In: The Scientific Basis of Toxicity Assessment, ed. H. Witschi, pp. 61- 67. Amsterdam: Elsevier/North-Holland Biomedical Press B.V. With P. W. Woodman and A. M. Sarrif. Specificity of pyrimidine

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298 BIOGRAPHICAL MEMOIRS nucleoside phosphorylases and the phosphorolysis of 5-fluoro- 2'-deoxyuridine. Cancer Res., 40:507-11. With S. I. Hannon, N. G. Kundu, R. P. Hertzberg, and R. S. Bhatt. A new synthesis of N-blocked dihydrouracil and dihydroorotic acid derivatives using lithium tri-sec-butyl borohydride as re- ducing agent. Tetrahedron Lett., 21: 1105-8. With P. W. Woodman and A. M. Sarrif. Inhibition of nucleoside phosphorylase cleavage of 5-fluoro-2'-deoxyuridine by 2,4- pyrimidinedione derivatives. Biochem. Pharmacol., 29:1059- 63. With E. B. Gehly, W. E. Fahl, and C. R. Tefcoate. Metabolism of benzofa~pyrene and oncogenic transformation in C3H/lOTl/2 mouse embryo fibroblasts. In: Microsomes, Drug Oxidations, and Chemical Carcinogenesis, vol. 2, ed. M. I. Coon, A. H. Conney, R. W. Estabrook, et al., pp. 1013-24. New York: Academic Press. Mammalian cell transformation and mammalian cell mutagenesis in vitro. l. Environ. Pathol. Toxicol., 3~4~:69-87. With A. R. Peterson and M. S. Fisher. Association between the cy- totoxicity of thymidine and tumorigenicity of clones derived from C3H/lOTl/2 mouse embryo fibroblasts. Biochem. Bio- phys. Res. Commun., 95:182-86. With A. M. Sarrif, H. Tone, and P. V. Danenberg. The incorpora- tion of trifluorothymidine into calf thymus DNA in a cell-free system does not lead to chain termination. Mol. Pharmacol., 18: 148-50. With }. R. Landolph and N. Telfer. Further evidence that ouabain- resistant variants induced by chemical carcinogens in trans- formable C3H/lOTl/2 C18 mouse fibroblasts are mutants. Mu- tat. Res., 72:295-310. With T R. Landolph, R. S. Bhatt, and N. Telfer. Comparison of adriamycin- and ouabain-induced cytotoxicity and inhibition of rubidium transport in wild-type and ouabain-resistant C3H/ lOTl/2 mouse fibroblasts. Cancer Res., 40:4581-88. With C. Boreiko, S. Mondal, and K. S. Narayan. Effect of 12-0- tetradecanoylphorbol- 13-acetate on the morphology and growth of C3H/lOTl/2 mouse embryo cells. Cancer Res., 40:4709-16. Oncogenic transformation, initiation, promotion and mutagenesis in C3H/lOTl/2 cells. In: Carcinogenesis: Fundamental Mechanisms

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CHARLES HEIDELBERGER 299 and Environmental Effects, ed. B. Pullman, P. O. P. Tsto, and H. Gelboin. Jerusalem Symp. Quantum Chem. Biochem., 13:311- 18. Boston: D. Reidel Publishing Co. With C. Boreiko. Isolation of mutants temperature-sensitive for expression of the transformed state from chemically trans- formed C3 H/ 1 OT 1/2 cells. Carcinogenesis, 1: 1059 -73. With A. Fernandez and S. Mondal. Probabilistic view of the trans- formation of cultured C3H/lOTl/2 mouse embryo fibroblasts by 3-methylcholanthrene. Proc. Natl. Acad. Sci. USA,77:7272- 76. . . . 1981 Cellular transformation as a basic tool for chemical carcinogenesis. In: Advances in Modern Environmental Toxicology. Vol. 1, Mammal- zan Cell Transformation by Chemical Carcinogens, ed. N. Mishra, V. Dunkel, and M. Mehlman, pp. 1-28. Princeton Junction, N.~.: Senate Press, Inc. Clinical molecular pharmacology. In: Accomplishments in Cancer Re- search, ed. I. G. Fortner and I. E. Rhoads, 1980 Prize Year, Gen- eral Motors Cancer Research Foundation, pp. 180-87. Phila- delphia: J. B. Lippincott. With R. S. Bhatt, N. G. Kundu, and T. L. Chwang. Synthesis of 5- ethynylorotic acid. I. Heterocycl. Chem., 18:771-74. With A. R. Peterson, J. R. Landolph, H. Peterson, and C. P. Spears. Oncogenic transformation and mutation of C3H/lOTl/2 clone 8 mouse embryo fibroblasts by alkylating agents. Cancer Res. 41 :3095-99. With P. V. Danenberg, M. A. Mulkins, and A. R. Peterson. The in- corporation of 5-fluoro-2'-deoxyuridine into DNA of mam- malian tumor cells. Biochem. Biophys. Res. Commun., 102: 654-58. With Y. Kubota, E. B. Gehly, and K. H. Link. Development of two cloned epithelial cell lines from normal adult mouse rat ventral prostates. In Vitro, 17:965-78. With P. V. Danenberg, R. S. Bhatt, H. G. Kundu, and K. Danen- berg. Interaction of 5-ethynyl-2'-deoxyuridylate with thymidy- late synthetase. I. Med. Chem., 24: 1537-40. Initiation and promotion, mutagenesis and transformation of C3H/lOTl/2 mouse embryo fibroblasts. Gann Monogr., 27: 207-19.

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300 BIOGRAPHICAL MEMOIRS 1982 With C. P. Spears, A. H. Shahinian, and R. G. Moran. In viva ki- netics of thymidylate synthetase inhibition in 5-fluorouracil- sensitive and -resistant murine colon adenocarcinomas. Cancer Res., 42:450-56. With M. A. Mulkins. Isolation of fluoropyrimidine-resistant mu- rine leukemic cell lines by one-step mutation and selection. Cancer Res., 42:956-64. With M. A. Mulkins. Biochemical characterization of fluoropy- rimidine-resistant murine leukemic cell lines. Cancer Res., 42: 965-73. With S. Mondal. Effects of tumor promoters on the differentiation of C3H/lOTl/2 mouse embryo fibroblasts. In: Carcinogenesas A Comprehensive Survey, vol. 7, ed. E. Hecker, N. E. Fusenig, W. Kunz, F. Marks, and H. W. Thielmann, pp. 391-94. New York: Raven Press. With E. B. Gehly, I. R. Landolph, H. Nagasawa, and ]. B. Little. Induction of cytotoxicity, mutation, cytogenetic changes, and neoplastic transformation by benzofa~pyrene and derivatives in C3H/lOTl/2 clone 8 mouse fibroblasts. Cancer Res., 42:1866- 75. With P. C. Billings. Effects of praziquantel, a new antischistosomal drug, on the mutation and transformation of mammalian cells. Cancer Res., 42:2692-96. With E. B. Gehly. Metabolic activation of benzofa~pyrene by trans- formable and nontransformable C3H mouse fibroblasts in cul- ture. Cancer Res., 42:2697 - 704. On the rational development of a new drug: The example of the fluorinated pyrimidines. Cancer Treatment Rep., 65 (suppl. 3~: 3-9. Relationship between carcinogenesis and transformation of cell cultures. In: Mechan~sms of Chemical Carcinogenests, ed. Curtis C. Harris and Peter A. Cerutti, pp. 563-73. New York: A. R. Liss. With E. B. Gehly. The induction of ouar-mutations in nontrans- formable CVP3SC6 mouse fibroblasts. Carcinogenesis, 3:963- 67. With R. G. Moran and P. V. Danenberg. Therapeutic response of leukemic mice treated with fluorinated pyrimidines and inhib-

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CHARLES HEIDELBERGER 301 itors of deoxyuridylate synthesis. Biochem. Pharmacol., 31: 2929-35. With P. C. Billings and A. O. Uwaifo. Rat hepatoma cells show ex- treme sensitivity to aflatoxin Be. Toxicol. Appl. Pharmacol., 66:297-304. With P. C. Billings and A. O. Uwaifo. Influence of benzoflavone on aflatoxin B~-induced cytotoxicity, mutation, and transformation in C3H/lOTl/2 cells. Cancer Res., 43:2659-63. With K. H. Link and J. R. Landolph. Chemical induction of ouar- mutants in an epithelial cell line. Environ. Mutagenesis, 5:33- 48. With I. R. Landolph, R. E. K. Fournier, A. Fernandez, and A. R. Peterson. Genetic and probability aspects of cell transformation by chemical carcinogens. Frog. Nucleic Acid Res. Mol. Biol., 29:87-98. With P. V. Danenberg and R. G. Moran. Fluorinated pyrimidines and their nucleosides. In: Advances in Enzymology and Related Areas in Molecular Biology, ed. Alton Meister, vol. 4, pp. 57 - 119. New York: John Wiley & Sons. In vitro carcinogenesis with cell lines. In: In Vitro Toxicity Testing of Environmental Agents, part A, pp. 305-15. New York: Plenum Press. With A. E. Freeman, R. I. Pienta, A. Sivak, et al. Cell transforma- tion by chemical agents A review and analysis of the litera- ture. Mutat. Res., 114:283-385. 1985 With A. R. Peterson and W. F. Benedict. Oncogenic transformation of C3H/lOTl/2 C1 8 mouse embryo fibroblasts by inhibitors of nucleotide metabolism. In: Genetic Consequences of Nucleotide Pool Imbalance, ed. F. J. deSerres, vol. 31, pp. 465-79. Basic Life Sci- ences, ed. A. Hollaender. New York: Plenum Press. With C. P. Spears, I. Shani, A. H. Shahinian, W. Wolf, and P. V. Danenberg. Assay and time course of 5-fluorouracil incorpo- ration into RNA of L1210/0 ascites cells in viva. Mol. Pharma- col., 27:302-7.

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302 BIOGRAPHICAL MEMOIRS PATENTS 1957 2,802,005 (August 6, 1957~. With R. Duschinsky. 5-Fluorouracil. 1959 2,835,396 (May 5, 19591. With R. Duschinsky. N-Glycosides of 5 fluorouracil. 1960 2,945,038 (July 12, 19601. With R. Duschinsky. 5-Fluorocytosine and preparation thereof. 2,948,725 (August 9, 1960~. With R. Duschinsky. 5-Fluoroorotic acid and preparation thereof. 1961 2,970,139 ~ January 31, 1961). With R. Duschinsky and W. G. Far- kas. 5-Fluorouracil nucleotides and preparation thereof. 1965 3,201,387. (August 17, 1965~. 5-Trifluoromethyluracil, derivatives thereof, and processes for preparing the same.

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