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Biographical Memoirs: V.58 (1989)

Chapter: Charles Heidelberger

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Suggested Citation:"Charles Heidelberger." National Academy of Sciences. 1989. Biographical Memoirs: V.58. Washington, DC: The National Academies Press. doi: 10.17226/1645.
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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

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

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

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

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.

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.

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.

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

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 days—in 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.

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-

CHARLES HEIDELBERGER 269 ical tests, and his extensive studies on the mechanism of ac- tion of the drug attest to a scientific breadth seldom achieved. PROFESSIONAL ACTIVITIES AND HONORS Heidelberger spent twenty-eight years at the McArcIle Laboratory, beginning as an assistant professor of oncology in 1948. He advanced to associate professor in 1952, profes- sor in 195S, ant! American Cancer Society Professor of On- cology in 1960. With the development of the Wisconsin Clin- ical Cancer Center in 1973, he became its associate director for basic science while continuing to maintain his appoint- ment at the McArdie Laboratory. In 1976 Heidelberger ac- ceptect the challenge of becoming the director for basic re- search of the Los Angeles County-University of Southern California Comprehensive Cancer Center. In this position he was responsible for organizing, recruiting new stab, and de- veloping the overall direction of research for a new cancer center. He was namer! a Distinguished Professor of the Uni- versity of Southern California in 1981. Although his un- timely death cut short his work, Heidelberger livecl to see the University of Southern California Comprehensive Cancer Center become a major center for cancer research. Heiclelberger gave generously of his time and intellect through membership on a number of professional commit- tees and participation in symposia and meetings. He was chairman of the biochemistry committee and a member of the drug evaluation pane! of the National Cancer Institute's Cancer Chemotherapy National Service Center ~ ~ 958- 19621; a member of the Pharmacology ant! Experimental Therapeutics B Study Section of the National Institutes of Health (1964-19681; a member for three terms of the boars! of (Erectors of the American Association for Cancer Research 959-962, ~965-l968, and ~976-l979~; a member of the U.S. National Committee of the International Union against

270 BIOGRAPHICAL MEMOIRS Cancer (1963-1970~; twice chairman of the program com- mittee for the American Association for Cancer Research ~ ~ 960 and ~ 96 ~ ); chairman of the program committee for the 1970 Tenth International Cancer Congress in Houston; a member of the program committee of the Eleventh Inter- national Cancer Congress in Florence, Italy, in 1974; a mem- ber of the Council of the International Union Against Cancer (1970-19741; a member of the Board of Scientific Counse- lors, Division of Drug Treatment, National Cancer Institute (1975-19781; a member of the fellowship committee of the International Union Against Cancer (1977-19781; a member of the fellowship committee of the International Agency for Research on Cancer, Lyon, France (1977-19781; and a mem- ber of the public issues committee of the American Associa- tion for Cancer Research (1977-19781. In 1978 he also served as a consultant to the government of the Federal Re- public of Germany during their organization of the Deutsche Stiftung fur Krebsforschung. In all of these activities, Hei- delberger displayer} a broad knowlecige of cancer research and alliecl fields, a perceptive mind, great organizational ca- pacity, tenacity, ant} willingness to work hard. He was recog- nized as a strong committee person who cli(1 his share of the work and expected others to clo likewise. Numerous awards came to Heidelberger for his research accomplishments: Langer-Teplitz Award for Cancer Re- search (1958), Lucy Wortham James Award of the lames Ew- ing Society ~969), Walter Hubert Lecturer of the British As- sociation for Cancer Research (1969), G.H.A. Clowes Award of the American Association for Cancer Research ~ ~ 970), An- nual National Awarcl of the American Cancer Society (1974), Lila Gruber Award of the American Academy of Dermatol- ogy (1976), Papanicolaou Award of the Papanicolaou Insti- tute for Cancer Research (1978), Founcler's Award of the Chemical Industry Institute of Toxicology ~1982), (I. Chester

CHARLES HEIDELBERGER 271 Stock Award of the Memorial SIoan-Kettering Cancer Center (1982), and Athayde International Cancer Prize of the Thir- teenth International Cancer Congress (19824. Heidelberger was elected to the National Academy of Sciences in 1978. With his election, his father, Michael Heidelberger, became one of the few members of the Academy to see his child also so honored. TEACHING Although Heidelberger did little formal teaching, he was well known and respected as a teacher. Over the course of his career, fourteen graduate students obtained the Ph.D. degree in his laboratory and a total of eighty individuals re- ceived postdoctoral training. He taught by example in the laboratory, through critical and in-depth discussions with his students, and by means of weekly meetings of his research staff. These meetings, which usually lasted several hours on Monday evenings, included discussion of all of the research in progress in the lab. Organic chemists learned about bio- logical problems, and biologists became familiar with discus- sions of synthetic organic chemistry. They all honed their critical thinking through listening and reacting to Heidelber- ger's probing. Heidelberger was a master at reporting scientific meetings to his colleagues on the staff, his students, and postdoctoral associates. He returned from each meeting with detailed notes from which he could reconstruct the main argument of a speaker's report and, usually, the critical data to support the claim, and few matched his ability to sum up and convey significant points to colleagues unable to attend. FAMILY AND SOCIAL ACTIVITIES In an autobiography written at the end of his high school years, Heidelberger pictured himself, especially prior to high

272 BIOGRAPHICAL MEMOIRS school, as a shy person. This description came as a surprise to Heidelberger's professional friends, who regarded him as strongly outgoing, somewhat aggressive, and very sociable. He enjoyed his family, and the Heidelbergers had a wide circle of friends. Their frequent social evenings might in- clude dinner, music, and wide-ranging discussions. Music was a highlight of Heidelberger's life. He learned to play the violin as a young boy, was a member of the Har- vard symphony orchestra in college, and continued to play chamber music throughout his life. Visits from his father, an amateur clarinetist, brought evenings of chamber music with family and friends. Heidelberger was also a jazz enthusiast. He played the trumpet and drums in jazz bands while in college and maintained his membership as a jazz trumpeter in the musicians' union for much of his life. This membership enabled him to introduce himself to professional musicians and join them for a tune or two while attending professional meetings. Heidelberger enjoyed his first visits to Europe as a young child and remained an avid traveler throughout his life. He and his wife often combined scientific meetings abroad with personal travel, making the most of the time available. He came home from England, Europe, Japan, parts of Asia, and Israel with hundreds of slides of scenery, people, and what- ever else fascinated him. These slides became his props for travelogues, both in the Heidelberger home and on several occasions- in the lecture room at McArdIe. Heidelberger's other major social activity was sailing, be- gun as a boyhood hobby in summer camp, nurtured during his years at Harvard, and later expanded with the purchase of a sailboat for use on Lake Mendota in Madison. His pas- sion for sailing culminated with the acquisition of a larger boat for sailing off the coast of southern California. Sailing

CHARLES HEIDELBERGER 273 and enjoying music with his family and friends were the ul- timate relaxation for this intensively active man. Heidelberger was married in 1943 to Judith Werble. Their three children are Nina Heidelberger Rosefelt, Philip Heidelberger, and Lisa Heidelberger. In 1975 he married Patricia Boshell, who together with his father, children, anti grandsons, Joshua Rosefelt and Davic! Charles Heidelberger, . . survives . film. Heidelberger died January 1 8, 1983, approximately eigh- teen months after a diagnosis of carcinoma of the nasal sinus. During the intervening period, except for periods of intense therapy, he continued his work. As in the case of his mother's death from breast cancer in 1946, which he cited as one of his reasons for going into cancer research, Heidelberger's illness intensified his concern to find an adequate chemo- therapy for cancer patients. Although he never achieved this ultimate goal, Charles Heidelberger's scientific accomplish- ments were impressive and earned him the recognition of his peers. His life was a full one, and he maintained strong re- lations with his family and friends. In his many former stu- dents and colleagues, in his research and accomplishments, Heidelberger has left a strong scientific le~rv ~ ~ , WE ARE INDEBTED to Michael Heidelberger for an account of Charles Heidelberger's early family life; to Patricia Heidelberger for information on his work at the University of Southern Califor- nia and for an autobiography written by Charles Heidelberger at the end of his high school education; and to our colleagues at the McArdle Laboratory, especially Henry C. Pitot, Van R. Potter, and Harold P. Rusch, for making their materials on Charles Heidelber- ger available to us.

274 BIOGRAPHICAL MEMOIRS SELECTED BIBLIOGRAPHY 1945 With H. Heymann. Derivatives of p,p'-diaminodiphenyl sulfone. II. I. Am. Chem. Soc., 67:1986-90. 1947 With P. Brewer and W. G. Dauben. The synthesis of 1,2,5,6- dibenzathracene labeled in the 9-position with carbon 14. I. Am. Chem. Soc., 69:1389-91. 1948 With L. F. Fieser, E. Berliner, F. J. Bondhus, E. C. Chang, W. G. Dauben, et al. Naphthoquinone antimalarials. I. General sur- vey. I. Am. Chem. Soc., 70:3151-55. With L. F. Fieser, E. Berliner, F. J. Bondhus, F. C. Chang, W. G. Dauben, et al. Synthesis. IV. Aryl side chains. V. Cycloalkylalkyl series. VI. 4'-Cyclohexylcyclohexyl and cycloalkyl series. VII. Unsaturated compounds. VIII. Aralkyl and substituted aralkyl series. IX. Aryl derivatives. X. Miscellaneous compounds with oxygen, halogen or nitrogen in the side chain. J. Am. Chem. Soc., 70:3175-215. With L. F. Fieser, F. C. Chang, W. G. Dauben, H. Heymann, and A. M. Seligman. Naphthoquinone antimalarials. XVIII. Meta- bolic oxidation products. I. Pharmacol. Exp. Ther., 94:85-96. With H. B. Jones. The distribution of radioactivity in the mouse following administration of dibenzanthracene labelled in the 9 and 10 positions with carbon 14. Cancer, 1:252-60. With M. Kirk and M. Perkins. The metabolic degradation in the mouse of dibenzanthracene labelled in the 9 and 10 positions with carbon 14. Cancer, 1:261-75. With M. E. Gullberg, A. F. Morgan, and S. Lepkovsky. Concerning the mechanism of the mammalian conversion of tryptophan into kynurenine, kynurenic acid and nicotinic acid. I. Biol. Chem., 175:471-72. With E. P. Abraham and S. Lepkovsky. Concerning the mechanism of the mammalian conversion of tryptophan into nicotinic acid. I. Biol. Chem., 176: 1461-62.

CHARLES HEIDELBERGER 275 1949 With M. Calvin, I. C. Reid, B. M. Tolbert, and P. E. Yankwich. Iso- topic Carbon. New York: I. Wiley & Sons. The synthesis of DL-tryptophan-,B-C~4, indole-3-acetic acid-(x-C~4 and DL tryptophan-3-C~4. J. Biol. Chem., 179: 139-42. With M. E. Gullberg, A. F. Morgan, and S. Lepkovsky. Tryptophan metabolism. I. Concerning the mechanism of the mammalian conversion of tryptophan into kynurenine, kynurenic acid and nicotinic acid. I. Biol. Chem., 179:143-50. With E. P. Abraham and S. Lepkovsky. Tryptophan metabolism. II. Concerning the mechanism of the mammalian conversion of tryptophan into nicotinic acid. I. Biol. Chem., 179:151-55. With V. R. Potter. Biosynthesis of "asymmetric" citric acid: A sub- stantiation of the Ogston concept. Nature (London), 164:180. 1950 With A. B. Pardee and V. R. Potter. The oxidation of acetate-l-C~4 by rat tissue in vitro. I. Biol. Chem., 186:625 - 35. With R. B. Hurlbert. The synthesis of oxalacetic acid-l-C~4 and orotic acid-6-C~4. I. Am. Chem. Soc., 72:4704-6. With V. R. Potter. Alternative metabolic pathways. Physiol. Rev., 30:487-512. With P. E. Wilcox and V. R. Potter. Chemical preparation of asym- metrically labeled citric acid. i. Am. Chem. Soc., 72:5019-24. 1951 With M. K. Brush, R. K. Boutwell, and A. D. Barton. Destruction of amino acids during filter paper chromatography. Science, 113:4-6. With G. A. LePage. Incorporation of glycine-2-C~4 into proteins and nucleic acids of the rat. i. Biol. Chem., 188:593-602. The application of the carbon isotopes to a study of animal metab- olism. Adv. Biol. Med. Phys., 2:77-131. With G. A. LePage. Incorporation of glycine-2-C~4 into purines of pentose nucleic acid and deoxyribose nucleic acid. Proc. Soc. Exp. Biol. Med., 76:464-65. With W. G. Wiest. The metabolic degradation in the mouse

276 BIOGRAPHICAL MEMOIRS of 1,2,5,6-dibenzanthracene-9,10-C~4. II. 5-hydroxy-1,2-naph- thalic acid, a new metabolize. Cancer Res., 11 :511-18. With H. S. Rieke. The synthesis of 3,4-benzpyrene-5-C~4 and of 2-acetylaminofluorene-9-C~4. Cancer Res., 11 :640 - 43. With V. R. Potter. Asymmetric citric acid. In: Isotopes in Biochemistry, Ciba Foundation Conference, pp. 246-56. London: J. and A. Churchill, Ltd. With S. M. Weiss. The distribution of radioactivity in mice fol- lowing administration of 3,4-benzpyrene-5-C~4 and 1,2,5,6- dibenzanthracene-9,10-C~4. Cancer Res., 11 :885-91. 1952 With G. A. LePage, V. R. Potter, H. Busch, and R. B. Hurlbert. Growth of carcinoma implants in fed and fasted rats. Cancer Res., 12:153-57. With E. P. Tyner and G. A. LePage. In vivo studies on incorpora- tion of glycine-2-C~4 into proteins and nucleic acid purines. Cancer Res., 12: 158-64. With E. C. Miller, A. M. Plescia, and I. A. Miller. The metabolism of methylated aminoazo dyes. I. The demethylation of 3'- methyl-4-dimethyl-Ci4-aminoazobenzene in viva. J. Biol. Chem., 196:863-74. With D. P. Groth, G. A. LePage, and P. A. Stoesz. Metabolism of pyruvate in tumor homogenates. Cancer Res., 12:529-34. 1953 With E. P. Tyner and G. A. LePage. Intracellular distribution of radioactivity in nucleic acid nucleotides and proteins following simultaneous administration Of pa and glycine-2-C~4. Cancer Res., 13:186-203. Applications of radioisotopes to studies of carcinogenesis and tu- mor metabolism. Adv. Cancer Res., 1:273-338. With H. I. Hadler and G. Wolf. The metabolic degradation in the mouse of 1,2,5,6-dibenzanthracene-9- 10-C~4. III. Some qui- none metabolites retaining the intact ring system. J. Am. Chem. Soc., 75:1303-8. With W. G. Wiest. The interaction of carcinogenic hydrocarbons with tissue constituents. I. Methods. Cancer Res., 13:246-49. With W. G. Wiest. The interaction of carcinogenic hydrocarbons

CHARLES HEIDELBERGER with tissue constituents. II. 1,2,5-6-dibenzanthracene-9-10-Cl4 in skin. Cancer Res., 13:250-54. With W. G. Wiest. The interaction of carcinogenic hydrocarbons with tissue constituents. III. 1,2,5,6-dibenzanthracene-9,10-C~4 in the submaxillary gland. Cancer Res., 13:255-61. Oxalacetic acid. Biochem. Prep., 3:59-61. 1954 With K. Moldave. Intramolecular heterogeneity in nucleic acid bio- synthesis. I. Am. Chem. Soc., 76:679-84. Discussion of biochemical tracer applications: Major problems, lim- itations, perspective and future objectives. In: Proceedings of the Second National Cancer Conference, vol. 2, pp. 1576-81. New York: American Cancer Society. 1955 With P. M. Bhargava. Partition chromatographic separation of aro- matic acids. I. Am. Chem. Soc., 77:166-68. With R. A. Keller. The effects of twenty-nine compounds on nu- cleic acid and protein biosynthesis in slices of Flexner-~obling carcinoma and rat spleen. Cancer Res., Suppl. 3: 106 - 12. With P. M. Bhargava and H. I. Hadler. Studies on the structure of the skin protein-bound compounds following topical applica- tion of 1,2,5,6-dibenzanthracene-9,10-C~4. I. 2-phenylphenan- threne-3,2'-dicarboxylic acid, a degradation product. }. Am. Chem. Soc., 77:2877-86. With K. C. Leibman. The metabolism of p32-labeled ribonucleo- tides in tissue slices and cell suspensions. J. Biol. Chem., 216: 823-30. 1956 The application of radioisotopes to the study of cancer induction. In: Proceedings of theInternational Conference on peaceful Uses of Atomic Energy, Geneva, August, 1955, vol. 10, pp. 435 - 39. With M. G. Moldenhauer. The interaction of carcinogenic hydro- carbons with tissue constituents. IV. A quantitative study of the binding to skin proteins of several C~4-labeled hydrocarbons. Cancer Res., 16:442 - 49. With E. Harbers, K. C. Leibman, Y. Takagi, and V. R. Potter. Spe- 277

278 BIOGRAPHICAL MEMOIRS cific incorporation of adenosine-5'-phosphate-32p into ribonu- cleic acid in rat liver homogenates. Biochim. Biophys. Acta, 20:445-46. Biochemistry of cancer. Annul Rev. Biochem., 25:573-612. With P. M. Bhargava. Studies on the structure of the skin protein- bound compounds following topical application of 1,2,5,6- dibenzanthracene-9,10-Ci4. II. Nature of the 2-phenylphenan- threne-3,2'-dicarboxylic acid-protein bond. I. Am. Chem. Soc., 78:3671-77. 1957 With N. K. Chaudhuri, P. Danneberg, D. Mooren, et al. Fluori- nated pyrimidines. A new class of tumor-inhibitory com- pounds. Nature (London), 179:663-66. With M. E. Baumann. Studies on OPSPA. I. The effect of several phosphoramides on transplanted tumors. Cancer Res., 17:277- 83. With R. K. Maller. Studies on OPSPA. II. Distribution and excre- tion of radioactivity following administration of OPSPA-C~4 and OPSPA-p32 to the rat. Cancer Res., 17:284-90. With R. K. Maller and F. A. McIver. Studies on OPSPA. III. Dis- tribution and excretion of radioactivity following administra- tion of OPSPA-C~4 and OPSPA-p32 to humans. Cancer Res., 17:291-95. With R. K. Maller. Studies on OPSPA. IV. Metabolism of OPSPA in the rat and human. Cancer Res., 17:296-301. With H. E. Skipper and A. D. Welch. Some biochemical problems of cancer chemotherapy. Nature (London), 179: 1159 - 62. With K. C. Leibman, E. Harbers, and P. M. Bhargava. The com- parative utilization of uracil-2-C~4 by liver, intestinal mucosa and Flexner-Jobling carcinoma in the rat. Cancer Res., 17:399- 404. With R. Duschinsky and E. Pleven. The synthesis of 5-fluoro- pyrimidines. I. Am. Chem. Soc., 79:4559-60. 1958 With L. Griesbach, O. Cruz, R. I. Schnitzer, and E. Grunberg. Fluorinated pyrimidines. VI. Effect of 5-fluorouridine and 5-

CHARLES HEIDELBERGER 279 fluoro-2'-deoxyuridine on transplanted tumors. Proc. Soc. Exp. Biol. Med., 97:470-75. With I. A. LaBudde. The synthesis of the mono- and dihydroxy derivatives of 1,2,5,6-dibenzanthracene excreted by the rabbit and of other hydroxylated dibenzanthracene derivatives. I. Am. Chem. Soc., 80:1225-36. With L. Griesbach, B. l. Montag, D. Mooren, et al. Studies on fluor- inated pyrimidines. II. Effects on transplanted tumors. Cancer Res., 18:305-17. With N. K. Chaudhuri and B. l. Montag. Studies on fluorinated pyrimidines. III. The metabolism of 5-fluorouracil-2-C~4 and 5- fluoroorotic acid-2-C~4 in vivo. Cancer Res., 18:318-28. With P. B. Danneberg and B. l. Montag. Studies on fluorinated pyrimidines. IV. Effects on nucleic acid metabolism in viva. Can- cer Res., 18:329-34. With L. Bosch and E. Harbers. Studies on fluorinated pyrimidines. V. Ejects on nucleic acid metabolism in vitro. Cancer Res., 18:335-43. With A. R. Curreri, F. l. Ansfield, F. A. McIver, and H. A. Wais- man. Clinical studies with 5-fluorouracil. Cancer Res., 18:478- 84. With M. E. Baumann. Negative data from cancer chemotherapy screening. In: Cancer Research Supplement on Cancer Chemotherapy Screening Data, pp. 373-76. Chicago: University of Chicago Press. With V. T. Oliverio. The interaction of carcinogenic hydrocarbons with tissues. V. Some structural requirements for binding of 1,2,5,6-dibenzanthracene. Cancer Res., 18: 1094-104. 1959 Studies on the mechanism of hydrocarbon carcinogenesis. Acta Unio Int. Contra Cancrum, 15: 107-13. The relation of protein binding to hydrocarbon carcinogenesis. In: Carcinogenesis, Mechanisms of Action, pp. 179-92. London: J. and A. Churchill Ltd. With N. K. Chaudhuri and K. L. Mukherjee. Studies on fluori- nated pyrimidines. VII. The degradative pathway. Biochem. Pharmacol., 1:328-41.

280 BIOGRAPHICAL MEMOIRS With E. Harbers. Studies on nucleic acid biosynthesis in Ehrlich ascites cells suspended in a medium permitting growth. I. Biol. Chem., 234:1249-54. With E. Harbers and N. K. Chaudhuri. Studies on fluorinated py- rimidines. VIII. Further biochemical and metabolic investiga- tions. I. Biol. Chem., 234:1255 - 62. With E. Harbers. Incorporation of labeled ribonucleoside-5'- monophosphates into ribonucleic acid in a cytoplasmic fraction of rat-liver homogenates. Biochim. Biophys. Acta, 35:381-88. With G. Kaldor. A new paper-chromatographic method for the separation of various pyrimidines and their deoxyribonucleo- sides. Biochim. Biophys. Acta, 36:249-50. 1960 With H. Ludwig, V. R. Potter, and C. H. de Verdier. Automatic direct quantitation of radioactivity on paper chromatograms. Biochim. Biophys. Acta, 37:525-27. With K. L. Mukherjee. Studies on fluorinated pyrimidines. IX. The degradation of 5-fluorouracil-6-C~4. I. Biol. Chem., 235: 433-37. With L. Griesbach and A. Ghobar. The potentiation by 5-iodo-2'- deoxyuridine (IUDR) of the tumor-inhibitory activity of 5- fluoro-2'-deoxyuridine (FUDR). Cancer Chemother. Rep. No. 6 (Feb.), pp. 37-38. With A. V. Sunthankar, L. Griesbach, and S. Randerson. Fluori- nated pyrimidines. XII. Effects of simple nucleotides on trans- planted tumors. Proc. Soc. Exp. Biol. Med., 104:127-29. With A. Ghobar, R. K. Baker, and K. L. Mukherjee. Studies on fluorinated pyrimidines. X. In vivo studies on tumor resistance. Cancer Res., 20:897-902. With G. Kaldor, K. L. Mukherjee, and P. B. Danneberg. Studies on fluorinated pyrimidines. XI. In vitro studies on tumor resis- tance. Cancer Res., 20:903-9. 1961 With G. R. Davenport. Local functional components of carcinogen- esis. Acta Unio Int. Contra Cancrum, 17:55 - 63. Biochemistry of human tumors. Nature (London), 189:627-28. With A. R. Somerville. The interaction of carcinogenic hydrocar-

CHARLES HEIDELBERGER 281 bans with tissues. VI. Studies on zero-time binding to proteins. Cancer Res., 21 :591-98. With G. R. Davenport and C. W. Abell. The interaction of carcin- ogenic hydrocarbons with tissues. VII. Fractionation of mouse skin proteins. Cancer Res., 21:599-610. Nucleic acid synthesis and mechanism of action of fluoropyrimi- dines. In: Biological Approaches to Cancer Chemotherapy, pp. 47- 58. New York: Academic Press. Experimental studies with the fluoropyrimidines. In: Research in Radiotherapy. Nuclear Science Series, Report no. 35. NASNRC Publ. 888, pp. 150-61. With K.-U. Hartmann. Studies on fluorinated pyrimidines. XIII. Inhibition of thymidylate synthetase. I. Biol. Chem.,236:3006- 13. With D. C. Remy and A. V. Sunthankar. Studies on fluorinated pyr- midines. XIV. The synthesis of derivatives of 5-fluoro-2'- deoxyuridine-5'-phosphate and related compounds. {. Org. Chem., 87:2491-500. 1962 With M. E. Baumann, L. Griesbach, A. Ghobar, and T. M. Vau- ghan. The carcinogenic activity of various derivatives of diben- zanthracene. Cancer Res., 22:78 - 83. With K. L. Mukherjee. Studies on fluorinated pyrimidines. XV. In- hibition of the incorporation of formate-Ci4 into DNA thymine of Ehrlich ascites carcinoma cells by 5-fluoro-2'-deoxyuridine- 5'-monophosphate and related compounds. Cancer Res., 22: 815-22. With N. I. Wagner. Some effects of 5-fluoroorotic acid and 5- fluorouracil on the soluble ribonucleic acid of rat liver. Biochim. Biophys. Acta, 61:373-79. With B. C. Giovanella and C. W. Abell. The preparation and pu- rification of tritiated hydrocarbons. Cancer Res., 22:925-30. With C. W. Abell. Interaction of carcinogenic hydrocarbons with tissues. VIII. Binding of tritium-labeled hydrocarbons to the soluble proteins of mouse skin. Cancer Res., 22:931-46. With D. Parsons and D. C. Remy. Synthesis of 5-trifluoro- methyluracil and 5-trifluoromethyl-2'-deoxyuridine. J. Am. Chem. Soc., 84:3597-98.

282 BIOGRAPHICAL MEMOIRS With F. F. Gollin, F. I. Ansfield, A. R. Curreri, and H. Vermund. Combined chemotherapy and irradiation in inoperable bron- chogenic carcinoma. Cancer, 15: 1209-17. 1963 With K. L. Mukherjee, l. Boohar, D. Wentland, and F. I. Ansfield. Studies on fluorinated pyrimidines. XVI. Metabolism of 5- fluorouracil-2-C~4 and 5-fluoro-2'-deoxyuridine-2-C~4 in cancer patients. Cancer Res., 23:49-66. With K. L. Mukherjee, A. R. Curreri, and M. Avid. Studies on fluorinated pyrimidines. XVII. Tissue distribution of 5-fluoro- uracil-2-C~4 and 5-fluoro-2'-deoxyuridine in cancer patients. Cancer Res., 23:67-77. With G. D. Birnie. In vitro synthesis of acid-soluble thymine com- pounds by human neoplastic tissues. Cancer Res., 23:420-30. With I. M. Lampkin-Hibbard and K. L. Mukherjee. Effects of ste- roids and fluoropyrimidines on lymphomas. II. In viva studies on tumor resistance and collateral sensitivity. Cancer Res., 23:468-76. With G. D. Birnie and H. Kroeger. Studies of fluorinated pyrim~- . dines. XVIII. The degradation of 5-fluoro-2'-deoxyuridine and related compounds by nucleoside phosphorylase. Bio- chemistry, 2:566-72. Biochemical mechanisms of action of fluorinated pyrimidines. Exp. Cell Res. Suppl., 9:462-71. With F. I. Ansfield. Experimental and clinical use of fluorinated pyrimidines in cancer chemotherapy. Cancer Res., 23: 1226-43. With G. D. Birnie, i. Boohar, and D. Wentland. Fluorinated pyrim- idines. XX. Inhibition of the nucleoside phosphorylase cleavage of 5-fluoro-2'-deoxyuridine by 5-trifluoromethyl-2'-deoxyuri- dine. Biochim. Biophys. Acta, 76:315-18. With H. C. Pitot. Metabolic regulatory circuits and carcinogenesis. Cancer Res., 23: 1694-700. With H. Gottschling. Fluorinated pyrimidines. XIX. Some biolog- ical effects of 5-trifluoromethyluracil and 5-trifluoromethyl-2'- deoxyuridine on Escherichia cold and bacteriophage T4B. J. Mol. Biol., 7:541-60. With K. H. Clifton, W. Szybalski, F. F. Gollin, F. I. Ansfield, and H. Vermund. Incorporation of I~25-labeled iododeoxyuridine into

CHARLES HEIDELBERGER 283 the DNA of murine and human tissues following therapeutic doses. Cancer Res., 23: 1715 -23. 1964 With D. G. Parsons and D. C. Remy. Syntheses of 5-trifluoro- methyluracil and 5-trifluoromethyl-2'-deoxyuridine. I. Med. Chem., 7:1-5. With B. C. Giovanella and L. E. McKinney. On the reported solu- bilization of carcinogenic hydrocarbons in aqueous solutions of DNA. I. Mol. Biol., 8:20-27. Rationale for the design of fluorinated pyrimidines. Acta Unio Int. Contra Cancrum, 20:39-40. With H. E. Kaufman. Therapeutic antiviral action of 5-trifluo- romethyl-2'-deoxyuridine in herpes simplex keratitis. Science, 145:585-86. Studies on the molecular mechanism of hydrocarbon carcinogen- esis. J. Cell. Comp. Physiol., 64 (suppl.~:129-48. Biochemistry of 5-fluorouracil. In: Chemotherapy of Cancer, ed. P. A. Plattner, pp. 88-98. New York: Elsevier. With S. W. Anderson. Fluorinated pyrimidines. XXI. The tumor- inhibitory activity of 5-trifluoromethyl-2'-deoxyuridine. Cancer Res., 24:1979-85. With l. Boohar and G. D. Birnie. Fluorinated pyrimidines. XXII. Effects of various compounds on the incorporation of formate- Cl4 into DNA thymine in suspensions of Ehrlich ascites cells. Biochim. Biophys. Acta, 91:636-38. With T. Boohar. Fluorinated pyrimidines. XXIII. Further studies on nucleoside phosphorylase. Biochim. Biophys. Acta, 91:639- 41. With M. E. Chang. The design and application of pyrimidine anti- metabolites for the control of nucleic acid metabolism. (In Rus- sian.) In: Molecular Biology, pp. 156-71. Moscow: Academy of Sciences USSR. 1965 With B. C. Giovanella. Mouse epidermal cells and carcinogenesis. I. Isolation of skin constituents. Cancer Res., 25: 161-84. With ~. Boohar and B. Kampschroer. Fluorinated pyrimidines. XXIV. In vivo metabolism of 5-trifluoromethyluracil-2-C~4 and

284 BIOGRAPHICAL MEMOIRS 5-trifluoromethyl-2'-deoxyuridine-2-C~4. Cancer Res., 25:377- 81. With P. Reyes. Fluorinated pyrimidines. XXV. The inhibition of thymidylate synthetase from Ehrlich ascites carcinoma cells by pyrimidine analogs. Biochim. Biophys. Acta, 103: 177-79. With P. Reyes. Fluorinated pyrimidines. XXVI. Mammalian thy- midylate synthetase: Its mechanism of action and inhibition by fluorinated nucleotides. Mol. Pharmacol., 1:14-30. Fluorinated pyrimidines: Biochemically and clinically useful anti- metabolites. In: Nucleic Acids, Structure, Biosynthesis, and Function, pp. 105-17. New Delhi: Council of Scientific and Industrial Research. Studies on the molecular mechanisms of hydrocarbon carcinogen- esis. (In russian.) Proc. Modern Biol. USSR, 59:101 - 13. With Y. Nishizawa, l. E. Casida, and S. W. Anderson. 3',5'-Diesters of 5-fluoro-2'-deoxyuridine: Synthesis and biological activity. Biochem. Pharmacol., 14: 1605 -19. Fluorinated pyrimidines. Prog. Nucleic Acid Res. Mol. Biol., 4: 1-50. On skin carcinogenesis and metabolism. Ann. Ital. Dermato. Clin. Sper., 19:153-67. 1966 With D. G. Parsons. Synthesis of Q-5-fluoro-2'-deoxyuridylyl- (5'- 5')-,13-5-fluoro-2'-deoxyuridine. i. Biol. Chem., 9:159. With M. -R. Roller and S. P. Owen. Studies on the organ culture of human tumors. Cancer Res., 26:626-37. With A. Dipple. Fluorinated pyrimidines. XXVIII. The synthesis of 5-trifluoromethyl-6-azauracil and 5-trifluoromethyl-6-aza-2'- deoxyuridine. l. Med. Chem., 9:715 -18. With H. Bujard. Fluorinated pyrimidines. XXVII. Attempts to de- termine transcription errors during the formation of fluoro- uracil-containing messenger ribonucleic acid. Biochemistry, 5:3339-45. With B. C. Giovanella. Studies on the molecular and cellular mech- anisms of hydrocarbon carcinogenesis. In: Advances in Biology of Skin, ed. W. Montagna, vol. 7, pp. 105-31. New York: Per- gamon Press.

CHARLES HEIDELBERGER 285 Fluorinated pyrimidines, biochemically and clinically useful anti- metabolites. In: Moleculare Biologie des Malignen Wachstums, pp. 155-76. New York: Springer-Verlag. 1967 With P. T. Iype. Malignant transformation in vitro by carcinogenic hydrocarbons. Science, 155 :214 -17. Cancer chemotherapy with purine and pyrimidine analogues. Annul Rev. Pharmacol., 7:101-24. Some reflections and speculations about chemical carcinogenesis. Can. Cancer Conf., 7:326-50. Oxford: Pergamon Press. With M. Umeda and T. A. Khwaja. Recent studies with fluorinated pyrimidines. In: Proceedings of the Fifth International Congress of Chemotherapy, Vienna, Austria, pp. 225-27. Basel: Karger. With N. Isenberg. Synthesis of 5-carboxy-2'-deoxyuridine. J. Med. Chem., 10:970-71. With R. Cavaliere, E. C. Ciocatto, B. C. Giovanella, et al. Selective heat sensitivity of cancer cells. Biochemical and clinical studies. Cancer, 20: 1351-81. With L. M. Goshman. Binding of tritium-labeled polycyclic hydro- carbons to DNA of mouse skin. Cancer Res., 27: 1678-88. With M.-R. Roller. Attempts to produce carcinogenesis in organ cultures of mouse prostate with polycyclic hydrocarbons. Int. }. Cancer, 2:509-20. With T. A. Khwaja. Fluorinated pyrimidines. XXIX. Syntheses of 2',3'-dehydro-5-fluoro-2'-deoxyuridine and 2',3'-dideoxy-5- fluorouridine. [. Med. Chem., 10: 1066-70. A rational approach to chemotherapy. Cancer Bull., 96-98. 1968 With P. T. Iype. Malignant transformation in vitro with carcino- genic hydrocarbons. In: Cancer Cells in Culture, ed. H. Katsuta pp. 351 - 63. Japan: University of Tokyo Press. With P. T. Iype. Characteristics of murine prostatic acid phospha- tase: Comparison with other tissues and species. Arch. Bio- chem. Biophys., 128:434-41. With P. T. Iype, M.-R. Roller, and T. T. Chen. Studies of hydrocar- bon carcinogenesis in organ and cell culture. In: Proliferation

286 BIOGRAPHICAL MEMOIRS and Spread of Neoplastic Cells, Twenty-first Annual Symposium on Fundamental Cancer Research, pp. 137-56. Baltimore: The Williams and Wilkins Company. With M. Umeda and T. A. Khwaja. Recent studies with fluorinated pyrimidines. Gann Monogr., 6:43-45. With M. Umeda. Fluorinated pyrimidines. XXX. Comparative studies of fluorinated pyrimidines with various cell lines. Can- cer Res., 28:2529 - 38. With M. Umeda and H. Diringer. Inhibition of growth of cultured cells by arginase and soluble proteins from mouse skin. Isr. J. Med.Sci.,4:1216-22. 1969 With M. Umeda. Fluorinated pyrimidines. XXXI. Mechanism of inhibition of vaccinia virus replication in HeLa cells by pyrimi- dine nucleosides. Proc. Soc. Exp. Biol. Med., 130:24-29. With P. Brookes. Isolation and degradation of DNA from cells treated with tritium-labeled 7, 1 2-dimethylbenz~a janthracene: Studies on the nature of the binding of this carcinogen to DNA. Cancer Res., 29:157 - 65. With T. T. Chen. Quantitative studies on the malignant transfor- mation of mouse prostate cells by carcinogenic hydrocarbons in vitro. Int. I. Cancer, 4:166 - 78. With T. A. Khwaja. Fluorinated pyrimidines. XXXII. Syntheses of 2',3'-dehydro-5-trifluoromethyl-2'-deoxyuridine and 5- trifluoromethyluridine. l. Med. Chem., 12 :543-45. With T. T. Chen. Cultivation in vitro of cells derived from adult C3H mouse ventral prostate. }. Natl. Cancer Inst., 42:903-14. With T. T. Chen. In vitro malignant transformation of cells derived from mouse prostate in the presence of 3-methylcholanthrene. J. Natl. Cancer Inst., 42:915-25. Quantitative studies on hydrocarbon carcinogenesis in vitro. In: Physico-Chemical Mechan~sms of Carcinogenes~s, [erusalem Symp. Quantum Chem. Biochem., 1:45-58. Jerusalem: Israel Acad. Sci. Humanities. With T. T. Chen and P. T. Iype. Malignant transformation in vitro with carcinogenic hydrocarbons. Adv. Enzyme Regul., 7:339- 49.

CHARLES HEIDELBERG,ER 287 With H. Diringer. 2-phenylphenanthrene-3,2'-dicarboxylic acid is not bound to mouse skin proteins after application of 1,2,5,6- dibenzanthracene: A retraction. Cancer Res., 29:2127-28. The need for additional alkylating agents and antimetabolites. Cancer Res., 29:2435-42. 1970 With T. A. Khwaja. Fluorinated pyrimidines. XXXIII. Synthesis of methylated 5-fluoro-2'-deoxyuridine derivatives. I. Med. Chem., 13 :64-69. With R. I. Kent and T. A. Khwaja. Fluorinated pyrimidines. XXXIV. Structure-activity studies of methylated 5-fluoro-2'- deoxyuridine derivatives. I. Med. Chem., 13:70-73. With H. Diringer and T. A. Khwaja. Fluorinated pyrimidines. XXXVI. Synthesis of some 2,4-substituted 5-trifluoro- methylpyrimidines. J. Med. Chem., 13: 151-52. With S. Mondal. In vitro malignant transformation by methylchol- anthrene of the progeny of single cells derived from C3H mouse prostate. Proc. Natl. Acad. Sci. USA, 65:219-25. With I. G. Tasseron, H. Diringer, N. Frohwirth, and S. S. Mirvish. Partial purification of soluble protein from mouse skin to which carcinogenic hydrocarbons are specifically bound. Biochemis- try,9:1636 - 44. With Y. Fujiwara and T. Oki. Fluorinated pyrimidines. XXXVII. Effects of 5-trifluoromethyl-2'-deoxyuridine on the synthesis of deoxyribonucleic acid of mammalian cells in culture. Mol. Phar- macol., 6:273-80. With Y. Fujiwara. Fluorinated pyrimidines. XXXVIII. The incor- poration of 5-trifluoromethyl-2'-deoxyuridine into the deoxy- ribonucleic acid of vaccinia virus. Mol. Pharmacol., 6:281-91. With R. }. Kent. Fluorinated pyrimidines. XXXV. The metabolism of 2',3'-dehydro-5-fluoro-2'-deoxyuridine in Ehrlich ascites cells. Biochem. Pharmacol., 19: 1095 -104. Studies on the cellular and molecular mechanisms of hydrocarbon carcinogenesis. Eur. I. Cancer, 6:161-72. Biochemical approaches to new cancer chemotherapeutic agents. In: Proceedings of the Sixth National Cancer Conference, pp. 599- 604. Philadelphia: J. B. Lippincott.

288 BIOGRAPHICAL MEMOIRS Chemical carcinogenesis, chemotherapy: Cancer's continuing core challenges. (G. H. A. Clowes Memorial Lecture.) Cancer Res., 30: 1549-69. With S. Mondal, P. T. type, and L. M. Griesbach. Antigenicity of cells derived from mouse prostate cells after malignant trans- formation in vitro by carcinogenic hydrocarbons. Cancer Res., 30: 1593-97. With B. C. Giovanella and W. A. Lohman. Effects of elevated tem- peratures and drugs on the viability of L-1210 leukemia cells. Cancer Res., 30: 1623-31. With B. C. Giovanella and I. Liegel. The refractoriness of the skin of hairless mice to chemical carcinogenesis. Cancer Res., 30:2590-97. With T. H. Corbett and W. F. Dove. Determination of the muta- genic activity to bacteriophage T4 of carcinogenic and noncar- cinogenic compounds. Mol. Pharmacol., 6:667-79. 1971 I. K. Selkirk and E. Huberman. An epoxide is an intermediate in the microsomal metabolism of the chemical carcinogen, di- benz~a,h~anthracene. Biochem. Biophys. Res. Commun., 43: 1010-16. With H. Higashi. Lack of effect of Warfarin (NSC-59813) alone or in combination with 5-fluorouracil (NSC-19893) on primary and metastatic L- 1210 leukemia and adenocarcinoma 755. Can- cer Chemother. Rep., 55:29-33. With P. L. Grover, P. Sims, E. Huberman, H. Marquardt, and T. Kuroki. In vitro transformation of rodent cells by K-region de- rivatives of polycyclic hydrocarbons. Proc. Natl. Acad. Sci. USA, 68: 1098-101. In vitro studies on the cellular and molecular mechanisms of hy- drocarbon carcinogenesis. In: Virus Y Cancer, Homenaje a ~ Duran-Reynals, ed. W. M. Stanley, J. Casals, J. Oro, and R. Se- gura, pp. 383 - 88. Barcelona: Imprenta Socitra. With T. Oki. Fluorinated pyrimidines. XXXIX. Effects of 5- trifluoromethyl-2'-deoxyuridine on the replication of vaccinia viral messenger RNA and proteins. Mol. Pharmacol., 7:653- 62. With A. Fridland and R. I. Langenbach. Purification of thymidy-

CHARLES HEIDELBERGER 289 late synthetase from Ehrlich ascites carcinoma cells. I. Biol. Chem., 246:7110-14. With S. Mondal, M. I. Embleton, and H. Marquardt. Production of variants of decreased malignancy and antigenicity from clones transformed in vitro by methylcholanthrene. Int. }. Can- cer, 8:410-20. With E. Huberman, L. Aspiras, P. L. Grover, and P. Sims. Muta- genicity to mammalian cells of epoxides and other derivatives of polycyclic hydrocarbons. Proc. Natl. Acad. Sci. USA, 68: 3195-99. With T. Oki and Y. Fujiwara. Utilization of host-cell DNA by vac- cinia virus replicating in HeLa cells irradiated intranuclearly with tritium. I. Gen. Virol., 13:401-13. With E. Huberman and l. K. Selkirk. Metabolism of polycyclic aro- matic hydrocarbons in cell cultures. Cancer Res., 31:2162-67. With T. Kuroki. The binding of polycyclic aromatic hydrocarbons to the DNA, RNA, and proteins of tranformable cells in culture. Cancer Res., 31:2168-76. 1972 With E. Huberman. The mutagenicity to mammalian cells of py- rimidine nucleoside analogs. Mutat. Res., 14: 130-32. With M. I- Embleton. Antigenicity of clones of mouse prostate cells transformed in vitro. Int. I. Cancer, 9: 8-18. With D. L. Dexter, W. H. Wolberg, F. J. Ansfield, and L. Helson. The clinical pharmacology of 5-trifluoromethyl-2'-deoxy- uridine. Cancer Res., 32:247-53. With T. Kuroki, E. Huberman, H. Marquardt, et al. Binding of K- region epoxides and other derivatives of benz~ajanthracene and dibenz~a,h~anthracene to DNA, RNA, and proteins of transformable cells. Chem.-Biol. Interact., 4:389-97. With H. Marquardt, T. Kuroki, E. Huberman, et al. Malignant transformation of cells derived from mouse prostate by epox- ides and other derivatives of polycyclic hydrocarbons. Cancer Res., 32:716-20. With H. Marquardt. Influence of "feeder cells" and inducers and inhibitors of microsomal mixed-function oxidases on hydrocar- bon-induced malignant transformation of cells derived from C3H mouse prostate. Cancer Res., 32:721-25.

290 BIOGRAPHICAL MEMOIRS With H. Marquardt. Stimulation of DNA snythesis in hydrocarbon- transformable hamster embryo cells by the K-region epoxide of benz~ajanthracene. Chem.-Biol. Interact., 5:69-72. With S. Nesnow, A. M. Mian, T. Oki, and D. L. Dexter. Fluorinated pyrimidines. XLI. Syntheses of 5-trifluoromethyl-3'-deoxyuri- dine and 5-fluoro-3'-deoxyuridine. I. Med. Chem., 15 :676-77. With T. Kuroki. Determination of the in-protein in transformable and transformed cells in culture. Biochemistry, 11:2116-24. The nucleotides of fluorinated pyrimidines and their biological ac- tivities. In: Carbon-Fluor~ne Compounds: Chemistry, Biochemistry, and Biological Activities, pp. 125-40. Ciba Foundation. Amster- dam: Elsevier-Excerpta Medical With E. Huberman, T. Kuroki, H. Marquardt, et al. Transforma- tion of hamster embryo cells by epoxides and other derivatives of polycyclic hydrocarbons. Cancer Res., 32: 1391-96. With R. l. Kent. Fluorinated pyrimidines. XL. The reduction of 5- fluorouridine-5'-diphosphate by ribonucleotide reductase. Mol. Pharmacol., 8:465-75. With R. I. Langenbach and P. V. Danenberg. Thymidylate synthe- tase: Mechanism of inhibition by 5-fluoro-2'-deoxyuridylate. Biochem. Biophys. Res. Commun., 48:1565-71. With P. V. Danenberg and R. I. Langenbach. Purification of thy- midylate synthetase from L. cased by affinity chromatography. Biochem. Biophys. Res. Commun., 49:1029-33. In vitro studies on the role of epoxides in carcinogenic hydrocar- bon activation. In: Topics in Chemical Carcinogenes~s, ed. W. Na- kahara, S. Takayama, T. Sugimura, and S. Odashima, pp. 371- 86. Tokyo: University of Tokyo Press. 1973 With P. Sims, P. L. Grover, T. Kuorki, et al. The metabolism of benz~ajanthracene and dibenz~a,h~anthracene and their related "K-region" epoxides, c~s-dihydrodiols and phenols by hamster embryo cells. Biochem. Pharmacol., 33: 1-8. With W. G. Thilly. Cytotoxicity and mutagenicity of ultraviolet ir- radiation as a function of the interval between split doses in cultured Chinese hamster cells. Mutat. Res., 17:287-90. With R. I. Palzer. Studies on the quantitative biology of hyper- thermic killing of HeLa cells. Cancer Res., 33:415-21.

CHARLES HEIDELBERGER 291 With R. J. Palzer. Influence of drugs and synchrony on the hyper- thermic killing of HeLa cells. Cancer Res., 33:422-27. Molecular biology and the mechanism of action of cancer chemo- therapeutic drugs. In: Chemotherapy of Malignant Neoplasms, 2d ea., ed. F.J. Ansfield, pp. 10-29. Springfield, Ill.: Charles C Thomas. S. Nesnow, T. Miyazaki, T. Khwaja, and R. B. Meyer, fir. Pyridine nucleosides related to 5-fluorouracil and thymine. l. Med. Chem., 16:524-28. With D. L. Dexter and T. Oki. Fluorinated pyrimidines. XLII. Ef- fect of 5-trifluoromethyl-2'-deoxyuridine on transcription of vaccinia viral messenger ribonucleic acid. Mol. Pharmacol., 9:283-96. With P. V. Danenberg. Synthesis of 5-trifluoromethyl-2'-deoxyuri- dine-5'-phosphate and 5-trifluoromethyl-2'-deoxyuridine-5'- triphosphate. l. Med. Chem., 1 6:7 1 2-1 4. With C. A. Reznikoff and D. F. Krahn. Malignant transformation of cells in culture using oncogenic chemicals. In: Tissue Culture Methods and Applications, ed. P. F. Kruse, fir., and M. K. Patter- son, fir., pp. 644-53. New York: Academic Press. Pyrimidine and pyrimidine nucleoside antimetabolites. In: Cancer Medicine, ed, J. F. Holland and E. Frei III, pp. 768-91. Phila- delphia: Lea Sc Febiger. With S. Nesnow. Pyridine nucleosides related to 5-fluorouracil. I. Heterocycl. Chem., 10:779-84. With I. R. Parkhurst and A. R. Peterson. Breakdown of HeLa cell DNA mediated by vaccinia virus. Proc. Natl. Acad. Sci. USA, 70:3200-4. Current trends in chemical carcinogenesis. Fed. Proc. Fed. Am. Soc. Exp. Biol., 32:2154-61. With H. Tone. Fluorinated pyrimidines. XLIV. Interaction of 5- trifluoromethyl-2'-deoxyuridine 5'-triphosphate with deoxyri- bonucleic acid polymerases. Mol. Pharmacol., 9:783-91. With C. A. Reznikoff and D. W. Brankow. Establishment and char- acterization of a cloned line of C3H mouse embryo cells sensi- tive to postconfluence inhibition of division. Cancer Res., 33:3231-38. With C. A. Reznikoff, J. S. Bertram, and D. W. Brankow. Quanti- tative and qualitative studies of chemical transformation of .

292 BIOGRAPHICAL MEMOIRS cloned C3H mouse embryo cells sensitive to postconfluence in- hibition of cell division. Cancer Res., 33:3239-49. Chemical oncogenesis in culture. Adv. Cancer Res., 18:317-66. 1974 With T. L. Chwang. Synthesis of a new pyrimidine nucleoside ana- log related to uridine. Tetrahedron Lett., 1 :95-98. With J. S. Bertram. Cell cycle dependency of oncogenic transfor- mation induced by N-methyl-N'-nitro-N-nitrosoguanidine in culture. Cancer Res., 34:526-37. With P. V. Danenberg and R. J. Langenbach. Structures of revers- ible and irreversible complexes of thymidylate synthetase and fluorinated pyrimidine nucleosides. Biochemistry, 13 :926-33. With A. R. Peterson and J. S. Bertram. DNA damage and its repair in transformable mouse fibroblasts treated with N-methyl-N'- nitro-N-nitrosoguanidine. Cancer Res., 34: 1592-99. With A. R. Peterson and J. S. Bertram. Cell cycle dependency of DNA damage and repair in transformable mouse fibroblasts treated with N-methyl-N'-nitro-N-nitrosoguanid~ne. Cancer Res., 34:1600-7. With A. R. Peterson and H. Peterson. The influence of serum com- ponents on the growth and mutation of Chinese hamster cells in medium containing aminopterin. Mutat. Res., 24:25-33. With N. G. Kundu. Cyclopentatf~isoquinoline derivatives designed to bind specifically to native deoxyribonucleic acid. III. Inter- action of 6-carbamylmethyl-8-methyl-7H-cyclopentaff]-isoqui- nolin-3~2H)-one with deoxyribonucleic acids and polydeoxy- ribonucleotides. Biochem. Biophys. Res. Commun., 60:561-68. Cell culture studies on the mechanisms of hydrocarbon oncogen- esis. In: Chemical Carcinogenes~s, part B. ed. P. O. P. Ts'o and I. A. DiPaolo, pp. 457-62. New York: Marcel Dekker, Inc. Conception logique et progres dans la chimiotherapie du cancer et des maladies a virus. Symbioses, 6:215-27. 1975 With A. M. Sarrif, J. S. Bertram, and M. Kamarck. The isolation and characterization of polycyclic hydrocarbon-binding pro- teins from mouse liver and skin cytosols. Cancer Res., 35: 816-24.

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.

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-

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

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

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

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

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.

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-

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.

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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Biographic Memoirs Volume 58 contains short biographies of deceased members of the National Academy of Sciences.

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