Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 258
OCR for page 259
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
OCR for page 260
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
OCR for page 261
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
OCR for page 262
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
OCR for page 263
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.
OCR for page 264
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.
OCR for page 265
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.
OCR for page 266
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
OCR for page 267
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.
OCR for page 268
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-
OCR for page 293
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.
OCR for page 294
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-
OCR for page 295
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
OCR for page 296
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
OCR for page 297
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
OCR for page 298
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
OCR for page 299
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.
OCR for page 300
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-
OCR for page 301
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.
OCR for page 302
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.
OCR for page 303
Representative terms from entire chapter:
biographical memoirs
