MINUTES
9TH NCI-JSPS JOINT STEERING COMMITTEE MEETING
Sheraton Anchorage, Alaska
June 26- 27, 1986

The meeting was called to order by Dr. Richard Adamson. He welcomed the members of the Joint Steering Committee to Anchorage, Alaska. He stated that it is appropriate to have the meeting of the US-Japan bilateral program, which has been progressively successful, in this frontier land. Dr. Adamson extended best wishes to Dr. Takashi Sugimura, who could not attend this meeting and hoped he would be able to see Alaska in the near future. Dr. Fuminori Sakai, Executive Director, JSPS, expressed his appreciation to Dr. Ihor Masnyk and Dr. Tsuyoshi Kakefuda for organizing this meeting. He also mentioned that the site of Alaska, a geographic center equally distant from the United States, Japan, and Europe, could become a center of scientific and cultural exchange. He stated that the close ties between the U.S. and Japan, which developed through this cooperation, have led to a significant advance in cancer research and treatment. He announced that Dr. Haruo Sugano will act as coordinator for the Etiology Program Area in place of Dr. Sugimura, as well as coordinator for the Interdisciplinary Program Area. Dr. Masnyk announced that the time schedules which were modified from the original agenda and compressed to one and a half days were accepted. Both sides agreed that the Progress Report for April 1 985 through March 1 986 will be assembled by the office of International Affairs, NCI, and compiled by JSPS for final printing in Japan.
Dr. Adamson was the first to report on the progress in the Etiology Program Area. During the last reporting period, three seminars were held. The first seminar was held in Hawaii on "Oncogenes and Experimental Carcinogenesis" which focused on the molecular mechanisms underlying cancer. New oncogenes discovered in experimental animals and human cancers and their activation mechanisms, and receter functions associated with cell growth, differentiation and malignancy were discussed. A second seminar was held in Japan and discussed "Causative and Modifying Factors in Digestive Tract Cancer." A third seminar was held in Hawaii, discussing "Oxygen Radicals in Cancer."
Five scientists came to the U.S. from Japan as Exchange Scientists in the areas of molecular biology, chemical carcinogenesis, and cytogenetics. The U.S. received 2 gms of dimethylimidazoquinoxaline and 3 gms of trimethylimidazoquinoxaline. Japan received 150 mgs of facapentaene-12 and 100 mgs of fecapentaene-14 under support from this program.
At the seminar entitled "Oncogenes and Experimental Carcinogenesis" the following new findings were presented. Two oncogenes, K- and N-ras; activated c-raf genes in the transformants induced by IQ, and that from human stomach cancer; I ca from a primary human hepatocellular carcinoma; chromosomal translocation associated with expression of c-myc oncogene; met oncogene closely linked to the locus responsible for cystic fibrosis; human c-ros-1 which encodes for a receptor for cell growth or differentiation; c-erbB-2/ neu gene and its relationship with EGF receptor; cellular ets genes and their clinical implication in human leukemias; a new oncogenes isolated from a human B cell lymphoma and from human stomach cancers.
Dr. Miller opened the discussion by asking whether oncogenes have anything to do with cancer frequencies. Cystic fibrosis, B cell lymphoma, and Wilms' tumor are frequent in the U.S. and Europe, whereas they are rare in Japan. Are these oncogene-related diseases less frequent in Japan because of less activation of the oncogenes? Dr. Adamson responded by suggesting that the activation of the oncogenes may play a part in the role of multiple processes required for carcinogenesis. Chromosomal rearrangement, which probably causes some genetic disorder, may be different among ethnic groups in the world, resulting in different frequencies of certain diseases. Different mutability is another possibility causing these differences. Dr. Hodes presented an example of transgenic experiments using cloned oncogenes or promoters of oncogenes demonstrating an extremely high frequency of malignant transformation in animals. Dr. Sugano stated that we do not have sufficient geo-epidemiological data related to the activation of oncogenes. However, it seems to be clear that some cancer types are closely associated with specific types of oncogenes, such as the erb gene activation with human adenocarcinoma of the stomach, intestine, and hepatocarcinoma. Dr. Adamson mentioned that some chemicals preferentially activate certain types of oncogenes. Whether activation of oncogenes is necessary or sufficient to generate malignant transformation is an open question.
The seminar on "Causative and Modifying Factors in Digestive Tract Cancer" was held under the US-Japan program. Discussion focused on the difference in incidence of digestive tract cancers in the U.S. and Japan. A number of new hypotheses concerning new promotive and antipromotive factors involved in chemical and environmental carcinogenesis, and a number of food preservatives related to the digestive tract cancers were discussed.
Subjects of this discussion covered: contributing factors of nitrosamines to human esophageal cancer; synergistic effects of BHA, BHT, and sodium ascorbate with MNNG on experimental stomach carcinogenesis; hyperproliferative states associated with GI cancers; promoting activity of NaCl in gastric carcinogenesis; effects of bile, bilic acid, fat-fiber, DMH, BHA, EQ, and sex hormones on experimental and human stomach and colon tumorigenesis; genetic control of susceptibility of rat gastric carcinogenesis; so-called "blocking agents" and "suppressing agents" for prevention of carcinogens; effects of drugs, pesticides, smoking, alcohol, and food additives on experimental liver and pancreatic cancers. The importance of primary prevention of cancer by adjusting the life-style proposed by Dr. Sugimura was introduced. Experimental data were presented, suggesting that physical exercise may contribute in the prevention of cancer.
The seminar on "Oxygen Radicals in Cancer" covered the following: DNA modification by oxygen radicals, namely, formation of 8-hydroxyguanine and its repair; oxidative DNA damage induced by endogenous oxygen radicals; N-OH-Trp-P2 generated oxygen radicals; formation of epoxidized 7, 8-dihydrodiol B(a)P by radicals generated in various biochemical systems; free radical formation of naphthylamines; superoxide generation and 8-OH-Gua in DNA by heated starch; oxygen radical formation and mutagenic activity in coffee; role of oxygen radicals in tumor promotion; suppressive effect of protease inhibitors on hydrogen peroxide in PMN cells; free radical in promotion and progression processes in mouse skin carcinogenesis; killing and induction of mutation of E. coli by hydrogen peroxide; induction of defense against oxidation; and epidemiological evidence of antioxidant protection against human cancer were discussed.
Although many chemical carcinogens were found to generate oxygen radicals and modify DNA, it is not yet proven to what extent this event is relevant to their carcinogenic potency. With accumulation of more data, a better overview on oxygen radicals in cancer should be obtained.
Dr. Miller questioned the effect of the usual amounts of free radicals on high-risk groups of diseases such as Down's syndrome with trisomication of the chromosome 21 where stiperoxide dismutase gene is located. Whether certain types of immune disorders, diabetes, juvenile rheumatic arthritis, and Alzheimer's disease can be connected to a high incidence of malignancies? Dr. Adamson responded by saying that the connections may be very difficult to fmd with a logical accuracy, but the amount of free radicals can be measured on these diseases by thymidine glycol or thymine glycol content in the urine. Oxidative DNA damage and repair frequencies of XP or other diseases can also be measured by the method Dr. Ames reported in the meeting. Absence of catalase in acatalasemia, a genetic disorder, may be of interest for future study. Different incidences of cancers in different portions of the gastrointestinal tract was discussed with genetic and environmental factors. Exposure to carcinogenic chemicals and physical agents, smoking, biochemical and functional aspects of organs, protective factors, and other various modifying factors are involved in the high- and low- incidence of cancers in humans. The danger of nonsmoking tobacco was discussed in relation to its high content of nitroso compounds. Dr. Sugano asked about the carcinogenic effect of alcohol consumption. Dr. Adamson mentioned a discrepancy between animal experiments, which indicate no carcinogenicity, while clear epidemiological evidence indicates that esophageal cancer is related to alcohol. A number of hypotheses suggest that alcohol as an effective solvent of carcinogens cause their higher effects, and lack of nutrition and contaminants in liquors are other contributing factors. An experimental result of methylnitrosourea that caused oral and esophageal cancer in monkeys was presented. The dose responded by prevention with vitamins, but not with an overwhelming dose of MNU administration.
In the Biology and Diagnosis Program Area three seminars were held. Dr. Hodes and Dr. Yamamura reported on the seminar "Analysis of Host Immune Response." This seminar was divided into three subareas: 1) The immunology and molecular biology of tumor antigens; 2) The biology of host-tumor interaction; and 3) Preclinical approaches to tumor immunology. Discussions were focused on the expression of oncogenes such as src and neu. The neu oncogene product-185 kd glycosylated phosphoprotein on the cell surface, monoclonal antibody against it, and transforming capability were described. The IL-2 receptor gene on human adult T cell leukemia; the role of an antibody against it; immune response mechanisms of normal and malignant cells; monoclonal antibodies which detected I-region encoded determinant of T cells; the lyrnphokine B cell stimulating factor-1; maturation of T cell; and transgenic mice experiments for the analysis of the T cell repertoire for xenogeneic histocompatibility gene products were described. The regulation of tumor cell growth by natural killer cells; retargeting of cytotoxic cells using cross-linked antibody heteroaggregates; IL-mediated tumor growth inhibition and skin graft rejection; tumor eradication by TCGF-independent T cell lines; cellular effector mechanisms involved in eradication of established tumor and tumor infiltrating lymphoid cells; systemic immunodeficiency as a model to the human AIDS pathology was discussed. Application of basic immune principles to preclinical tumor immunology including LAK system; ricin A linked antibodies for immunotherapy; biologic response modifiers, and hepatic muramyldipeptide derivatives were described. Dr. Yamamura summarized the major topics of the meeting stating a number of highlights of the following: expression of oncogene and antitumor antibodies which can modulate the cell growth and malignant cell phenotypes; immunotherapeutic modalities; biochemical purification of tumor specific antigens; and immunological property of natural killer cells. The meeting was concluded as being a highly successful and informative one.
Dr. Adamson questioned dose response and modality effects of IL-2 and IL-2 plus LAK cell systems. The toxicity of IL-2, cost, manpower resources, etc., are difficult problems, but it is clearly worthwhile to pursue for further investigation. Dr. Ogawa mentioned that Japanese doctors who have been trying to follow the Dr. Rosenberg's procedure had some technical difficulties. Current progress of this treatment at the NCI was presented. AIDS, Kaposi's disease, and other immunodeficiency diseases in relation to adenosine deaminase, were discussed. Dr. Hodes explained details of transgenic experiments in response to a question raised by Dr. Sugano. Potential applications of the methodology to immunodeficiency diseases were suggested.
The seminar on "Lymphoid Markers and their Genes" was held on January 31-February 3, 1986, at Sapporo, Japan. The T cell receptor and accessory molecules (T3) complex; T4 and T8 glycoproteins; role of T4 in AIDS; T4 gene expression in normal human brain; characterization of the expression of the IL-2 and IL-2 receptors; B cell stimulatory factors; B cell differentiation antigens with respect to B cell malignancies; surface antigens and cytokines of NK cells; analysis of tumor necrosis factor in human; B-lymphocyte differentiation associated with gene assembly and rearrangement; myc and ras genes involved in lymphoid transformation; BSF-1, BCGF and BCDF; abl oncogene in muri'ne and human leukemia; and sensitive recipient cell lines for DNA transfection were discussed.
The seminar on "Regulation of Expression and Function of Retroviral Transformation-related Genes" was held February 17-19, 1986, at Hawaii. The sac gene and other tyrosine kinase coding genes; abl and other related oncogenes; genes for growth factors and their receptors; Gproteins and ras gene products; and X-genes of BLV/HTLV-I family and their expression and function were the major topics of discussion. Amino and DNA sequence homology in between src family oncogenes and EGF receptor; sea and erb oncogene products; two different modes of activation of cabl associated with viral transduction and chromosome translocation; temperature sensitive phenotype induced in A-MuLV by 5-Azacytidine; myristylation in virus assembly and in transformation by abl and src; reversible phosphorylation regulated by extracellular signals (EGF); EGF receptor regulation by PDGF mediated by phosphorylation by protein kinase C or an unknown kinase; the effect of monoclonal antibody to p 1 85 (neu product); translocation of human ets-l gene; DNA binding protein encoded by pX gene of HTLV-I which may have a regulatory mechanism of the oncogene expression; yes oncogene function; and hepatocyte growth factor were also discussed.
Four scientists came to the U.S. from Japan and one U.S. scientist visited Japan under the auspices of this program area. Dr. Miller mentioned that the incidence of retinoblastoma is low in Japan and very high in India. Etiological background behind the characteristic epidemiological pattern is interesting in terms of the oncogene activation problem.
The Treatment Program Area supported three seminars. A seminar on "Combined Modality of Chemotherapy and Radiotherapy" was held October 10-11, 1985, in Tokyo. Attention was focused on both disease site oriented issues and new modality applications.
Platinum-based chemotherapy combined with radiation; control of breast cancer; current methods for treating small cell and non-small cell lung cancer, gastrointestinal, genitourinary, gynecologic tumors for maximizing interrelationship between chemotherapy and radiation in order to minimize toxic side effects; preclinical techniques to reduce inherent drug and radiation resistance; new drug screening method for radiation sensitization and for maximizing combination chemotherapy effects; radioprotectors; hyperthermia; and high energy particle were discussed. The meeting opened a highly valuable and friendly relationship and scientific information exchange among cancer chemotherapists and radiotherapists in the U.S. and Japan.
Dr. Sugano asked a question regarding the communication among surgeons, radio-therapists, and chemotherapists in the U.S. Drs. Friedman and Hodes replied by saying that at most medical institutions, particularly at NIH, the intercommunication between medical oncologists, radiologists, and others is often quite successful at the educational, research, and clinical levels, but not invariably so.
The seminar on "Clinical Trial Methodology" was held on January 30- 31, 1986 in Hawaii. Statistical and regulatory aspects of new therapy development were discussed in detail.
Special attention was given to the recently proposed Japanese guidelines for testing new agents in Phase I and Phase II situations and comparisons made to U.S. evaluation of new products; methodology to evaluate biologic response modifiers; Phase III trial methodology which are necessary for product approval in the respective Federal agencies; adjuvant therapy of breast and gastric cancers; and statistical methodology for effective evaluation of treatments. Importance of the relationships between research oncologists and industry were also strongly emphasized. Dr. Ogawa stated that the drug evaluation system being applied in Japan is markedly different from that in U.S.
The seminar on "New Drug Development and Regional Chemotherapy" was held on March 24-25 at NCI, Bethesda. New anthracycline analogues, platinum analogues, antimetabolites and deoxycoformycin were discussed with their efficiency and toxicities. Topics related to intraarterial therapy, biologic response modifiers, circumvention of drug resistance, and monoclonal antibody were presented.
Four scientists came to the U.S. as Exchange Scientists under the Treatment Program Area. Two of them were scheduled to stay up to one year. The Interdisciplinary Program Area supported two seminars. The seminar on "Cancer Epidemiology in Southeast Asia" was held December 1 2-13, 1985, in Honolulu. Dr. Miller stated that the purpose of the meeting was to explore differences between the U.S. and Japan in the frequencies of certain cancers and compare them with studies that have been made in Southeast Asia (SEA) under the Nakasone Cancer Program.
The topics discussed were: Adult T cell leukemia in SEA; cancer frequencies in different ethnic groups in Western and Asian countries; diet and genetic effects on the susceptibilities for cancers in different countries; cancer frequencies among Caucasians, Blacks, Japanese, and Filipinos in the U.S. as compared with others who did not migrate; XP complementation groups in SEA; hepatitis B and hepatocellular carcinoma in relation to so-called R and S type hepatocytes; schistosomiasis related to bladder cancer; lung cancer case-control studies in Japan and Hong-Kong; and chromosomal pathogenesis relevant to carcinogenesis among different ethnic groups.
The epidemiological studies as discussed in the meeting will provide new opportunities for laboratory and clinical investigations. The route of ATL/HTLV-I, which presumably diffused from the West into Asian countries and became endemic or its prehistoric existence, as claimed by a group of Japanese scientists, was discussed with hypothetical possibilities of the migration. The occurrence in isolated clusters is a peculiar puzzle. A comprehensive study on this peculiar disease including epidemiology, molecular biology, immunology, and clinical investigation combined would be an interesting issue that the US-Japan Cancer Program may take for serious consideration for future discussion.
The seminar on "Recent Advances in Bladder Cancer Research" was held on March 24-25, 1986, at Nagoya, Japan.
Discussions concerned the high incidence of bladder cancer in, Japanese migrants to the U.S.; close association of bladder cancer with cigarette smoking, occupation and coffee drinking; isolation and characterization of bladder cancer oncogene; altered Ha-ras and neu genes in 10-30 percent of bladder cancer; diagnostic use of monoclonal antibodies; bladder cancer promoting substances; results of various treatments; and concanavalin-A agglutination assay which correlated with tumor promotion activity. Hyperthemia and interferon as effective treatment for bladder cancer have been noted.
Three Exchange Scientists visited the U.S. and one scientist visited Japan for current information exchange under the auspice of the Interdisciplinary Program Area.
Large discrepancies exist between diffuse and nodular types of lymphoma among patients in the U.S. and Japan. Hodgkin's disease is an another example of the significant difference between the two countries. The true value of the international program is to recognize the difference and similarity and solve the problems by cooperative efforts using available scientific resources of both countries.

FUTURE PLANS
Eleven future seminars or symposia were envisioned, three in Japan and eight in the U.S. Seventeen scientists will be involved in the exchange scientist program, thirteen from Japan, and four from the U.S. A limited exchange of materials is being planned.
Planned Seminars in the Etiology Program Area for FY 87:
1. Risk Estimation of Chemical Carcinogenesis. February or March 1987, in Hawaii.
2. Transacting Factors in Viral Carcinogenesis. March 1987, in Tokyo or Kyoto.
3. Marine Products and Cancer Research. March 1987, in Hawaii.
Planned Seminars in the Biology and Diagnosis Program Area:
1. Regulatory Elements in Normal and Transformed Cells. February 12-14, 1987, in Hawaii.
2. Immunogenic Analysis of Host Response of Tumors. November 1986, in Seattle.
3. Oncogenes and Tumor Antigens. November, 1986, in Seattle.
Planned Seminars in the Treatment Program Area:
1. Current Status of Bone Marrow Transplantation. November 1986, in Tokyo.
2. Innovative Approaches to Adjuvant and Neo-adjuvant Therapy. January 1986, in Hawaii.
3. Pharmacologic and Biochemical Mechanisms of Insensitivity to Therapy. March 1897, in Bethesda.
Planned Seminars in the Interdisciplinary Program Area:
1. Hepatitis B Virus in Liver Cancer. January 29-30, 1987, in Hawaii.
2. Genetics in Human Cancer. March 23-25, 1987, in Los Angeles.
Proposed Exchange Scientists.