( RESEARCH 50. 7405-7409. November 15. 1990)

Meeting Report and Chemotherapy—Cancer's Continuing Core Challenges: Third Charles Heidelberger Symposium1

Dr. Charles Heidelberger (1920-1983) devoted his entire delberger was able to attend the symposium and to share working life to and made outstanding contri memories of Charlie with us. butions in the areas of cancer and chemical carcinogenesis. According to his words (1), these parallel threads of research are "cancer's continuing core challenges." Keynote Lecture Dr. Heidelberger was a pioneer in the development of antime- The program of 38 scientific presentations was commenced tabolic drugs for the treatment of cancer. He introduced a with a keynote lecture given by Dr. T. Sugimura (National fluorine atom into uracil to produce 5-FU,2 a standard com Cancer Center, Tokyo, Japan) on "multiple genetic alterations during carcinogenesis." Dr. Sugimura summarized the multiple ponent of long standing, used in several protocols for the treatment of solid . His contributions to chemi genetic alterations observed in human cancers, which include cal carcinogenesis include the synthesis of radioactive polycyclic point , rearrangements, sequence deletions, gene am aromatic hydrocarbons in the 1940s, the binding of polycyclic plification, and integration of viral . Through these alterations, activation of and inactivation of antion- aromatic hydrocarbons to cellular macromolecules in the 1950s cogenes occur, resulting in the acquisition of malignant phe- and 1960s, and the development of mammalian transfor mation in vitro in the C3H/10T'/2 cell line in the 1960s and notypes. Multiple genetic alterations are commonly found in many cancers, but the patterns of alterations vary depending 1970s. on origins and histological types of the cancers, with some The symposium held at the International Conference Hall, specificities being observed. Kyoto, Japan, from December 10 to 13, 1989, was the third commemorating Charles Heidelberger's contributions to cancer research. It followed on the success of two previous symposia Session 1: Cell Differentiation organized by his former postdoctoral fellows. The first, on the Dr. Y. Nagai (University of Tokyo, Tokyo, Japan) reported role of chemicals and radiation in the etiology of cancer, was on the significance of "B-pathway" gangliosides in the regula organized by Dr. E. Huberman (Argonne National Laboratory', tion of neural cell growth and differentiation. Among B-path Argonne, IL) and was held from August 26 to 29, 1984, in way gangliosides (GD.„GD2,Gmb, GTn,, and Gyu,), GDj and Oakbrook, IL (2). The second, on transformation and differ G0ib are found to increase in association with the proliferation entiation in vitro, was organized by Dr. J. S. Bertram (Cancer of neuronal cells at the embryonic stage and also with active Research Center of Hawaii, University of Hawaii, Honolulu, gliosis. Exogenous Gylb enhances neurite outgrowth of human HI) from February 9 to 12, 1988, in Honolulu, HI (3). The cell lines. His observation provides evidence purpose of the third symposium, held in Kyoto, was to discuss that GD.Iand GQib of B-pathway gangliosides are of particular in depth the two areas of research initiated and developed by- importance in relation to cell growth and differentiation in Charles Heidelberger, i.e., carcinogenesis and chemotherapy. neural and possibly to its malignancy. The organizing committee' invited speakers from among Dr. Dr. P. A. Jones (University of Southern California, Los Heidelberger's former postdoctoral fellows, colleagues, and Angeles, CA) reported on the relationship between the meth- those who are extending the research he initiated. The sympo ylation and expression of the MyoDl muscle determination gene in C3H/10T'/: cells. The MyoDl gene is more methylated sium was open for a limited number (about 150) of participants. in C3H/10T'/2 cells than in myogenic derivatives. In addition, We were honored by the presence of Her Royal Highness Chulabhorn of Thailand and fortunate that Mrs. Patricia Hei- transformation results in a marked stimulation of the methyl- ation of the determination gene. The abilities of chemical Received 7/2/90; accepted 8/8/90. to perturb DNA methylation patterns may there 'This symposium was held in Kyoto. December 10-13, 1989 at the Kyoto fore be important in silencing genes known to elicit the differ International Conference Hall, Kyoto, Japan. The Osaka Foundation for Pro motion of Fundamental Medical Research and Taiho Pharmaceutical Co., Ltd.. entiation of cells. supported its organization locally while travel of United States participants was Dr. E. Huberman (Argonne National Laboratory, Argonne, sponsored by the following organizations: Bristol-Myers Co.. Pharmaceutical Research and Development Division: The Proctor & Gamble Co.. Miami Valley IL) has been studying early biochemical events that cause Laboratories: The Upjohn Co.. Pharmaceutical Research and Development Di alterations in leading to terminal differentia vision; Sterling Drug. Inc., a subsidiary of Eastman Kodak: The National Institute tion of human promyelocytic cells, HL-60. He found of Environmental Health Sciences; The Department of Energy, Office of Health and Environmental Research; Argonne National Laboratory/The University of that a number of early events, such as subcellular translocation Chicago; and The University of Texas M. D. Anderson Science Park. and activation of PKC, phosphorylation of , and mod 2The abbreviations used are: 5-FU. 5-fluorouracil; TPA. 12-O-tetradecanoyl- phorbol-13-acetate; PKC. kinase C: XP. xeroderma pigmentosum; G- ulation of topoisomerase II activity, may be early steps in the CSF, granulocyte colony-stimulating factor; cDNA, complementary DNA. preceding the induction of cell differentia 3Members of the organizing committee were: Toshio Kuroki (University of tion and by phorbol esters. Tokyo, Tokyo, Japan), (the late) Setsuro Fuji! and Tetsuhiko Shirasaka (The Osaka Foundation for Promotion of Fundamental Medical Research, Osaka, Dr. T. Nakamura (Kyusyu University, Fukuoka, Japan) pre Japan). Toshikazu Oki (Bristol-Myers Research Institute, Ltd., Tokyo. Japan), sented data on molecular cloning of hepatocyte Shigeru Tsukagoshi (Cancer Chemotherapy Center, Japanese Foundation for and its relevance in liver regeneration. This growth factor is a Cancer Research, Tokyo. Japan), Thomas J. Slaga. (M. D. Anderson Cancer Center. Science Park, Smithville, TX), and Eliezer Huberman (Argonne National heterodimer composed of an «-chain(A/r 69,000) and a ß-chain Laboratory, Argonne. IL). (M, 34,000). Both «-and 0-chains are contained in a single 7405

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1990 American Association for Cancer Research. MEETING REPORT open reading frame coding a protein with 728 amino acids, ylation in tumor promotion which can be regulated by the from which the mature heterodimer structure is derived by balance of protein kinases and protein phosphatases. proteolytic cleavage. Its mRNA was detected in nonparenchy- Dr. T. Kuroki (University of Tokyo, Tokyo, Japan) described mal cells of injured liver, suggesting paracrine action of hepa- his work on the purification and characterization of target tocyte growth factor. proteins of PKC in tumor promotion systems in vivo and in cell Cadherin-mediated cell adhesion in normal and transformed culture. In mouse skin in vivo and keratinocytes in culture, M, cells was reported by Dr. M. Takeichi (Kyoto University, Kyoto, 34,000 and M, 40,000 proteins (p34 and p40) are phosphory- Japan). Cadherins, a family of transmembrane glycoproteins lated by PKC at the serine residue. p40 was identified as creatine responsible for Ca2+-dependent intercellular adhesion, were phosphokinase B. It was found, also, that and discovered and cloned by Takeichi and his colleagues. The of mouse skin overexpress "secondary" response amino-terminal 113-amino acid region of the extracellular do genes which are induced 4 h or more after TPA treatment (e.g., main of the molecule is important in determining the specific metallothionein, osteopontin, and urokinase), while the early ities. The intracellular domain is anchored to the cytoskeleton. responding nuclear oncogenes in these tumors remain at low The finding that tumor cell lines with greater metastatic activity levels similar to those in normal skin. express smaller amounts of cadherin suggests possible involve Dr. G. T. Bowden (University of Arizona, Tucson, AZ) ment of cadherins in . reported on differential gene expression in multistage carcino genesis. Using differential and subtractive hybridization of cDNA libraries he was able to identify five cellular genes that Session 2: Tumor Promotion/Gene Expression are overexpressed at different stages of mouse skin TPA, an example of phorbol ester tumor promoters, activates esis. One of these genes, called transin or stromelysin encodes PKC and is known to induce expression of the nuclear onco- a secreted, metalloproteinase which may degrade proteins of genes c-fos and c-jun, the products of which cooperate in the the basement membrane and may play a functional role in of many TPA-inducible genes. It is therefore malignant tumor cell . A similar gene, matrix metal assumed that alterations of signal transduction and gene expres loproteinase 7, was found to be overexpressed in primary and sion are involved in tumor promotion. metastatic human prostatic adenocarcinoma compared to be Dr. T. J. Slaga (University of Texas M. D. Anderson Cancer nign prostatic and normal prostate. Center, Smithville, TX) described cellular and molecular Dr. H. Herschman (University of California, Los Angeles, changes during skin tumor progression. Papillomas start as CA) described the isolation and characterization of cDNAs for diploid lesions, but between 10 and 20 weeks of promotion, a group of TPA-induced primary response genes. By sequencing papillomas begin to contain more hyperdiploid cells. Trisomy the cDNAs it was demonstrated that these genes include tran of 6 followed by trisomy of chromosome 7 are the scription factors and cytokines. All these genes are also induced primary and sole cytogenetic abnormalities found in papillomas by polypeptide , such as epidermal growth factor and and some carcinomas. More progressed carcinomas have tri fibroblast growth factor, in 3T3 cells. somies of 2 and 13 also. These chromosomal changes may be responsible for changes in specific oncogenes Session 3: Target Molecules in Carcinogenesis and differentiation-related genes. The importance of gap-junctional communication in trans Dr. R. Langenbach (National Institute of Environmental formation and carcinogenesis was reported by Dr. H. Yamasaki Health Sciences, Research Triangle Park, NC) reported trans- and Dr. J. S. Bertram. Dr. Yamasaki (International Agency for fection of the gene for cytochrome P450IA1 and the cDNAs Research on Cancer, Lyon, France) reported that transformed for cytochromes P450IIA3 and IIE1 into the human lympho- cells reduce their communication with the normal cells that blastoid line AHH-1. Cells containing the cytochrome P450IA1 surround them, indicating that this may be important for the had about 3-fold greater mutagenic response to B|. maintenance of transformed . Expression of the Cells containing cytochromes P450IIA3 and IIE1 were sensitive connexin (gap junction protein) gene is reduced in hyperplastic to dimethylnitrosamine-induced , whereas the par nodules and in carcinomas of rat livers. Their results indicate ent nontransfected cells were refractory. that communication acts as a tumor-suppressive pressure and Dr. S. Nesnow (United States Environmental Protection damage to the communication plays a role in carcinogenesis. Agency; Research Triangle Park, NC) was unable to attend the Dr. J. S. Bertram (University of Hawaii, Honolulu, HI) also symposium but joined us by sending an abstract. He provided presented studies indicating regulation of transformation by information on the relationship between DNA adduci forma gap-junctional communication. Transformed C3H/10T'/2 cells tion and morphological cell transformation by benz[y] do not constitutively communicate with nontransformed cells; aceanthrylene, a component of coal combustion emissions, and however, after elevation of cyclic AMP levels these cells junc- its presumptive reactive intermediates in C3H/10T'/2 cells. The tionally communicate and become G, arrested. Retinoids cause DNA adduct patterns and morphological transformation re dramatic increases in homologous junctional communication. sults suggested two routes of metabolic activation: diol-epoxide Their ability to inhibit transformation strongly correlates with and cyclopenta-ring oxide, with the former pathway predomi their ability to up-regulate gap-junctional communication. nating. A new pathway of tumor promotion by okadaic acid was Dr. H. Kasai (National Cancer Center Research Institute, reported by Dr. H. Fujiki (National Cancer Center Research Tokyo, Japan) found that the formation of 8-hydroxydeoxygu- Institute, Tokyo, Japan). Okadaic acid binds to and inhibits anosine is one of the major consequences of damage to DNA serine/threonine-specific protein phosphatases, resulting in ap bases caused by ionizing radiation and other oxygen radical- parent activation of protein kinases and further leading to forming agents. This adduct may cause mutagenesis and carci tumor promotion in mouse skin and rat glandular stomach. nogenesis since it induces misreading during in vitro synthesis These results demonstrate the importance of protein phosphor- of DNA. Because 8-hydroxydeoxyguanosine can be readily 7406

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1990 American Association for Cancer Research. MEETING REPORT measured by high-pressure liquid chromatography coupled to SV40 replication system, camptothecin formed topoisomerase an electrochemical detector, it can be used as a marker for I-DNA-cleavable complexes, which are convened into irrevers monitoring oxidative DNA damage. ible double-strand breaks. He proposed that the "collision" The incidence of skin cancers is very high in XP patients between drug-trapped cleavable complexes and replication forks owing to a defect(s) in an early step during DNA excision leads to fork arrest and possible fork breakage. repair. Dr. K. Tanaka (Osaka University, Osaka, Japan) has Dr. S. Asano (University of Tokyo, Tokyo, Japan) reported finally cloned the DNA repair gene which complements the the therapeutic use of human G-CSF, a M, 19,000 glycoprotein defect of DNA excision repair in group A XP cells (XPAC which specifically stimulates the production and functional gene). mRNA of the XPAC gene is absent in almost all the activation of . Phase II/III clinical studies revealed group A XP cell lines tested but present in groups B to H, that daily single injections of recombinant human G-CSF variant XP, and normal human cells. Southern blot analysis shorten the period of neutropenia after bone marrow transplan revealed no gross gene rearrangements in the XPAC gene of tation and cancer chemotherapy with a reduction in the risk of group A XP cells, suggesting that the in group A XP infectious complications. G-CSF is also effective in the treat cells may arise from a (s), a small (s) in ment of chronic neutropenia. the exons, or splicing abnormalities. Two papers were presented on the repair mechanism of Oh- There are several drugs which, while not themselves killing cancer cells, potentiate the chemotherapy efficacies of various alkyldeoxyguanosine. Using highly specific monoclonal anti anticancer drugs. Dr. S. Tsukagoshi (Japanese Foundation for bodies, Dr. J. Thomale (University of Essen, Essen, Federal Cancer Research, Tokyo, Japan) reviewed clinical trials of these Republic of Germany) has been analyzing the formation and potentiators. For example, combinations of 5-FU and metho- subsequent enzymatic repair of DNA alkylation products by N- trexate or leucovorin are being applied currently in the treat nitroso compounds and investigating their relevance to carci- nogenesis. He found that O"-alkylguanine repair-proficient var ment of solid tumors of gastrointestinal tracts and with better results being reported. iants of 208F rat fibroblasts are more resistant to malignant One of the important problems in cancer chemotherapy is conversion by /V-ethyl-TV-nitrosourea than the repair-deficient clones, indicating the direct involvement of O6-ethylguanine in intrinsic and acquired multidrug resistance. It is now under stood that P-glycoprotein, encoded by the MDRÕgene, causes cell transformation. multidrug resistance via an energy-dependent drug efflux mech Dr. M. Sekiguchi (Kyushu University, Fukuoka, Japan) has recently cloned cDNA for repair of 06-methyldeoxyguanosine. anism. Dr. K. Ueda (Kyoto University, Kyoto, Japan) isolated Because purification of 06-methylguanine-DNA methyltrans- the region and cDNA of the MDR1 gene from mul- tidrug-resistant cells and from human normal tissue and found ferase from mammalian cells was extremely difficult. Dr. Sek several changes in the protein- but not iguchi transfected a cDNA library prepared from repair-profi cient cells into repair-deficient cells and subsequently cloned in the promoter region. Dr. P. Danenberg (University of Southern California, Los the repair gene. The predicted amino acid sequence of the Angeles, CA) studied the mechanism of acquired resistance to human methyltransferase exhibits marked homology with those 5-fluoro-2'-deoxyuridinein FM3 A mouse mammary of bacterial counterparts, especially around possible methyl cells. The acquisition of resistance was characterized by step- acceptor sites. wise changes in involved in 5-fluoro-2'-deoxyuridine Dr. J. K. Selkirk (National Institute of Environmental Health Sciences, Research Triangle Park, NC) used two-dimensional metabolism and activity. The first step was amplification of the gene for thymidylate synthase, the target of the fluo- gel electrophoresis to characterize gene products of transform able C3H/10T'/2 cells, transformation-resistant cells, and trans ropyrimidines. As the amount of this amplification leveled off, formed cells. Utilizing computerized image analysis of digitized the activity of thymidine kinase decreased. Genetic analysis protein patterns, it was determined that there was a significant disclosed a 29-base pair deletion in exon 6 of the thymidine variance in the number and type of modulated proteins in all kinase gene, probably resulting in a truncated thymidine kinase three cell lines. protein being generated. 5-FU has recently reemerged as a key drug in the systemic treatment of colon cancer, in particular in combination with Session 4: Cancer Chemotherapy leucovorin. Dr. F. M. Muggia (University of Southern Califor Although cancer chemotherapy was a major research area of nia, Los Angeles, CA) reported on a clinical trial designed to determine the maximally tolerated dose of 5-FU when given on Dr. Heidelberger, the two previous memorial symposia focused a continuous intravenous schedule coupled with weekly leuco on another of his research areas. In this conference, we invited vorin. A dose of 20 ml/m2 leucovorin weekly could be safely eight speakers for the session on cancer chemotherapy, a field in which there are new and exciting recent developments. combined with 28 days of 5-FU given in a continuous daily infusion of 200 ml/m2. It is now being compared to other Dr. Y. Uehara (National Institute of Health, Tokyo, Japan) screened for agents which reverse the transformation by Rous regimens in advanced gastrointestinol tumors. Leucovorin with . The antibiotic herbimycin was found to inhibit 2-deoxy-5-fluorouridine is also being studied by the i.p. route the functions of the src and reverse malignant phe- in ovarian cancers. notypes of ire-transformed cells. Although herbimycin has not The presentation of Dr. E. Mihich (Roswell Park Cancer yet been proven useful for cancer chemotherapy because of Institute, Buffalo, NY) was dedicated to the memory of the late toxicity, this study has provided a potential method for screen Professor Setsuro Fujii, a member of the organizing committee ing new drugs acting against cells expressing oncogene. who, sadly, passed away on August 4, 1989. Dr. Mihich re Dr. F. Liu (Johns Hopkins University, Baltimore, MD) re ported enhancement of the therapeutic effect of 5-FU by com ported on the topoisomerase I-targeting antitumor drug, camp- bined use with leucovorin. Metabolic modulation of 5-FU by tothecin, which specifically kills S-phase cells. In a cell-free these protocols indicates that natural resistance to 5-FU can be 7407

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1990 American Association for Cancer Research. MEETING REPORT reversed in cancer patients by increasing the intracellular pools epithelial cells, Dr. C. C. Harris (National Cancer Institute, of reduced folates. Bethesda, MD) found that oncogenes, either a single gene or a combination of them, dysregulate pathways of growth and Session 5: Transformation in Vitro differentiation, leading to . The im portance of tumor suppressor genes was indicated by the obser Dr. Heidelberger early foresaw the possible importance of vation of allelic loss of certain genes in lung tumors, suggesting and cell cultures for obtaining insight into carcinogenesis. that oncogenes and tumor suppressor genes play key roles in After spending a sabbatical year in 1962 at the laboratory of human lung carcinogenesis. Dr. Lasnitzski in England, he established cell transformation Dr. M. S. Sasaki (Kyoto University, Kyoto, Japan) focused systems using mouse prostate cells and the C3H/10T'/2 cell on the origin of mutation in the Rb gene in and line, the latter of which has long been used extensively in studies osteosarcoma. Germ line mutations of the Rb gene are strongly on transformation and differentiation. biased in favor of a paternal origin. In sporadic unilateral Dr. C. Borek (Columbia University, New York, NY) dis , the initial somatic mutation of the Rb gene, cussed the identification of activated oncogenes in radiogenic seem to be equally attributable to a contribution from either transformation of the C3H/10T/2 cells and demonstrated the maternally or paternally derived chromosomes. importance of reactive oxygen and the arachidonic acid cascade Dr. M. Noda (Institute of Physical and Chemical Research, in the multistep neoplastic process. Dr. Borek showed that Tsukuba, Japan) used a unique approach to identify tumor thyroid , which acts as a co-transforming factor in the suppressor genes that are able to revert a transformed pheno C3H/10T'/2 cells, mediates its action in part by stimulating type of v-K-ras-transformed NIH/3T3 cells. A series of K-rev arachidonate metabolism. By contrast, nutritional antioxidants genes encoding a ras-related protein were isolated from a human act as anticarcinogens, in part, by inhibiting free radical me cDNA library. Site-directed mutation of these genes indicates diated lipid peroxidation and suppressing certain stages in the that K-rev protein is regulated, like G-proteins, by a GTP/GDP arachidonic acid cascade. exchange mechanism probably in response to certain negative Dr. J. Landolph (University of Southern California, Los growth-regulatory signals. Angeles, CA) showed that c-myc expression is frequently in A superfamily of ras p2\/ras p2I-like small GTP-binding creased in chemically transformed 10T1/: cell lines and likely proteins (G-proteins) and their cDNA clones were isolated by participates in maintaining the transformed , Dr. Y. Takai (Kobe Univeristy, Kobe, Japan). Evidence is nickel, and chromium compounds induced transformation of accumulating that this family of G-proteins constitutes a huge C3H/10T'/2 cells and also anchorage independence in human network of intracellular regulatory systems. In particular, smg diploid fibroblasts without immortality or morphological p21 was found to be identical with K-m'-l protein isolated as changes. Since this assay also detects noncarcinogenic trivalent a by Noda et al. Dr. Takai and his chromium and soluble nickel compounds, more stringent assays associates also isolated a GTPase-activating protein and a novel are needed for detecting metal-induced transformation in hu GDP dissociation inhibitor. The activities of raíp2l/ras p21- man diploid cells. like G-proteins appeared to be regulated by these regulatory Dr. P. Nettesheim (National Institute of Environmental proteins. Health Sciences, Research Triangle Park, NC) reported the role For identification of human chromosomes carrying tumor of peptide growth factors in neoplastic progression of trans suppressor genes. Dr. M. Oshimura (Kanagawa Cancer Center, formed rat trachea! epithelial cells. Transformed cell lines show- Yokohama, Japan) isolated mouse A9 cells containing a single decreased requirements for bovine pituitary extract, insulin, human chromosome with integrated pSV2neo plasmid DNA. and epidermal growth factor compared to normal primary cells By transfer of a human chromosome into various tumor cell and expressed significantly increased levels of mRNAs of trans lines, he identified human chromosomes that can suppress or forming growth factors a and ß.Hisstudies suggest that aber modulate tumor-associated phenotypes of the cells. The intro rant expression of growth factors may play an important role duction of chromosome 1 suppressed the tumorigenicities of in the development and maintenance of the transformed phe various human tumors, suggesting that normal human chro notype. mosomes carry tumor suppressor gene(s) involved in negative control of the growth of certain tumor cells. Dr. E. J. Stanbridge (University of California, Irvine, CA) Session 6: Tumor Suppressor Genes presented further evidence for the existence of tumor suppressor Evidence for tumor suppressor genes comes from a variety genes that may regulate, negatively, the growth of tumor cells. of studies including somatic cell hybrids, chromosome/gene He identified a cell surface antigen. p75/150, in tumorigenic transfer, and accumulating evidence of gene deletions in human segregants of HeLa x human diploid hybrids. cDNA cloning cancers. Thus, it is now generally recognized that dominantly of p75/150 revealed that this surface protein was intestinal acting oncogenes and tumor suppressor genes play important alkaline phosphatase. Their data suggest that differential roles in the genesis of human cancer. expression of p75/150 is due to transcriptional regulation. Using hybrids between human diploid fibroblasts and im The presentation of Dr. W. F. Benedict (Baylor College of mortal Syrian hamster cell lines. Dr. J. C. Barrett (National Medicine, Woodlands, TX) was dedicated to the late Professor Institute of Environmental Health Sciences, Research Triangle Takeo Kakuiia.ua. a noted scientific colleague who was present Park, NC) found that human chromosome 1 may participate at the first two Heidelberger symposia. Dr. Benedict discussed in the control of cellular . He provided evidence the role of the Rb gene not only in the development of retino demonstrating that the tumor suppressor gene in immortal but also in more common human cancers such as hamster cells negatively regulates the growth response of cells those of the bone, breast, and lung. Future studies will allow in agar to mitogenic stimuli. not only the determination of the significance of finding a loss By of various oncogenes into human broncheal of Rb function within a given tumor but also whether this loss 7408

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1990 American Association for Cancer Research. MEETING REPORT of function results in a worse prognosis for a given tumor. Shimizu (Bristol-Myers Research Institute, Tokyo, Japan). Naotaka Dr. Heidelberger's deep concern for the problems associated Nishiyama (Taiho Pharmaceutical Co., Ltd., Tokyo, Japan), Karen Champbell-Engel (University of Texas, M. D. Anderson Cancer Center, with cancer and the energy and enthusiasm with which he Smithville, TX), and Sara A. Bechtold (Argonne National Laboratory, sought the cause of cancer and pursued its treatment were never Argonne, IL). ending. The willingness with which he adopted new approaches Toshio Kuroki and techniques both stimulated and provided a model for his Institute of Medical Science students, postdoctoral fellows, and colleagues. The participants University of Tokyo at this symposium attested to his continuing influence on the Shirokanedai, Minato-ku, current exciting developments that are taking place in cancer Tokyo 108, Japan research. We hope that further Heidelberger symposia will be held, thus providing a unique opportunity for the better under standing of molecular and cellular mechanisms of carcinogen- References esis and chemotherapy. 1. Heidelberger. C. Chemical carcinogenesis. chemotherapy: Cancer's continu ing core challenges—G. H. A. Clowes memorial lecture. Cancer Res., 30: 1549-1569. 1970. Acknowledgments 2. Huberman. E. (ed.). The Role of Chemicals and Radiation in the Etiology of Cancer, Carcinogenesis—a Comprehensive Survey, Vol. 10. New York: Raven Press, 1985. The organizers wish to acknowledge the secretarial assistance of 3. Bertram. J. S. Meeting Report: Second Heidelberger conference on transfor Noriko M. Shishido (University of Tokyo, Tokyo, Japan). Taeko mation and differentiation in vitro. Cancer Res.. 49: 2814-2817. 1989.

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Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1990 American Association for Cancer Research. Carcinogenesis and Chemotherapy−−Cancer's Continuing Core Challenges: Third Charles Heidelberger Symposium

Toshio Kuroki

Cancer Res 1990;50:7405-7409.

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