MINUTES
10TH NCI-JSPS JOINT STEERING COMMITTEE MEETING
Miyako Hotel, Kyoto, Japan
June 25-26, 1987

The meeting was called to order by Dr. Fuminori Sakai at 9 a.m. He welcomed the members of the Joint Steering Committee of the 14th U.S.-Japan Cooperative Cancer Research Program. The Program has been highly productive and has made significant contributions to the advancement of biomedical sciences. Mr. Yasushi Murao, who has replaced Mr. Onozawa as the Executive Secretary, introduced himself and announced that he will chair this session.
Dr. Adamson expressed his delight to be in a well organized and nicely accommodated meeting by the JSPS in Kyoto. He mentioned that he is particularly happy to be in the ancient capital of Japan which not only is the cultural, economic and political center but also is the city which was fully protected during World War II under a Presidential Order issued by Franklin Roosevelt. The U.S.-Japan Cancer Program is one of the best of the NCI bilateral programs and is always productive in exchanging current scientific information, scientists and research materials. He noted regrets that Dr. Miller, who has long attended these meetings, could not participate at this time because of an illness. He hoped for Dr. Miller’s quick recovery and return to the Program. Dr. Adamson will act as coordinator for the Etiology Program Area as well as Interdisciplinary Program Area.
Mr. Murao announced that the modified time schedules compressed to one day were accepted.
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 “Marine Products and Cancer Chemoprevention” and focused on biology, chemistry and pharmacology of tumor promoters and inhibitors of tumor promoters from natural sources in particular those from marine organisms. Presented at the seminar was a review of two distinct types of promoters, one of which activates protein kinase C through binding to a receptor, and the other that elicits biological responses without activation of protein kinase C. A review of biological active toxins of marine products with tumor promoting potential from different sources was also presented. Synergistic and non-synergistic activities with toxins and growth factors and their receptor functions were suggested as involved in the tumor promoting mechanisms. Non-TPA type promoters derived from marine products appear to induce tumor promotion by a different pathway. Derivatives of retinoid and other compounds were also discussed in terms of their inhibitory activities of tumor promotion.
Dr. Sugimura mentioned that this particular seminar has an unique background because Drs. Moor and Fujiki, the co-organizers of the meeting, have been collaborating during the past 10 years. Both teleocidines and aplysiatoxins found in marine products and in fungus are potent tumor promoters and are distinct in chemical structure from TPA, but share the same phorbol ester receptor in mouse cells. On the other hand, okadaic acid, also found in a black sponge is a non-TPA type promoter, and does not share the same receptor. Many marine products were found to be potent tumor promoters and others were inhibitors. Dr. Sugimura and others suggested that many cancer therapeutic agents may be found in marine products in different areas of the sea, some of which have already been used in research and clinical treatment. Nevertheless, the studies carried out almost entirely in the United States and Japan are a typical example of successful international cooperation in cancer research.
The seminar entitled “Transacting Factors in Viral Carcinogenesis” was held in Kyoto. The seminar discussed and exchanged information on the molecular and genetic mechanisms involved in transcriptional transactivation of a group of viruses in carcinogenic progression. Transactivating factors involved in the regulation of gene expression of the bovine papilloma virus, human papilloma virus, adenovirus, polyoma virus, EBV, SV40 virus, and HSV-I were discussed. Special attention was focused on the pX regions of HTLV-I, HTLV-II and bovine leukemia virus. The exchange of scientific information among specialists of retrovirus and DNA viruses in relation to the malignant transformation and the AIDS problem was particularly valuable.
The seminar on “Risk assessment of Environmental Carcinogenic Factors” was held in Hawaii. The methodology of hazard identification, exposure assessment, dose-response assessment and characterization of carcinogenic risk with human exposure to environmental carcinogens were the subject of extensive discussion. The NCI Toxicology Program, contribution of mechanistic studies on the risk evaluation, new methodologies for identification and risk evaluation of mutagens and carcinogens, epidemiological studies, risk estimation of radiation-induced cancer based on the data from atomic bomb survivors, chromosomal abnormalities and sister chromatid exchanges as parameters for human risk, effects of long-term lifestyle on cancer progression, pharmacokinetics and pharmacodynamics for risk assessment were presented. This seminar was the first time information was exchanged on the methodology of risk assessment and its limitations. How recent technology of epidemiology and laboratory data can be used effectively for risk assessment is a major subject of future investigation.
Dr. Sugimura mentioned that although discovery of new carcinogens in the laboratory is an important issue, proper assessment of carcinogens on human risk is equally important in a sense of public health care. The United States side presented the risk evaluation methodology with epidemiological investigations and mathematical models, while the Japanese side discussed mostly the laboratory data. It was a extremely valuable opportunity to exchange the scientific information of different views from both countries at this seminar.
Three scientists came to the United States from Japan as Exchange Scientists in the areas of metabolic pathway of nucleotide analogues (Dr. Y. Wataya), analysis of chromosome with DNA probes and anti-oncogene study (Dr. J. Yokota), and advanced methodology for the detection of DNA modification (Dr. K. Yamashita).
Two materials were exchanged for collaborative studies between the NCI and National Cancer Center of Japan.
Dr. Yamamura initiated the discussion of the activities in the Biology and Diagnosis Program Area. Two seminars—“Cellular and Molecular Mechanisms of Oncogenesis and Cancer Immunity” and “Regulatory Element in Normal and Transformed Cells”-- were held jointly, with 30 scientists from both countries participating. Six major topics were the subject of extensive discussion. The immunoglobulin genes and immunoglobulin receptors and their regulation were discussed in the first session. Identification and partial characterization of the genes involved in recognition and activation of T lymphocytes were discussed in the second and third sessions. The lymphokines and their receptors, regulation of IL-2 and IL-2 receptors, B cell stimulatory factors, presence of T cell specific tyrosine kinase gene, and many other topics were discussed in the fourth and fifth sessions. The last session covered the pre-clinical and clinical trial of the tumor immunology including LAK cells, NK cells, and cytotoxic T cells. Dr. Hodes mentioned that the joint meeting on immunology and diagnosis was thought by all participants to be especially productive, and the format may be useful for future planning of seminars under the U.S.-Japan Cancer Program. Discussions were extensive and highly productive. In particular, interaction between immunologists and molecular biologists concerned with similar areas of cell biology and tumor biology was extremely useful.
Another meeting on “Regulatory Element in Normal and Transformed Cells” was held in Hawaii on February 10- 13, 1987. Dr. D, Baltimore gave a general review on the regulation of immunoglobulin gene. The participants generally agreed on the present understanding that the genetic expression in eukaryotic cells are controlled by multiple control mechanisms, rather than a single mechanism. Each one of them interacts with more than one transacting factor. This complex network of regulatory machinery is present in normal genes and oncogenes. Much scientific evidence supporting this general concept was presented and discussed extensively in the session. Further studies directed toward elucidating the complex regulatory mechanisms of normal and cancer cells are considered to be an essential importance. From this point of view, the sharing of ideas and suggestions in a small meeting was felt to be a worthwhile experience by all participants. Highly distinguished scientists from the United States and Japan have participated in this successful meeting. However, conducting a meeting in prime season in Hawaii was difficult and resulted in less desirable accommodations for participants. The OIA promised to investigate alternative possibilities for better administrative and logistic support.
Dr. Ogawa asked about the United States evaluation of the NK cell therapeutic system established by Dr. S. Rosenberg. Drs. Friedman and Hodes said that the response to the NK cell treatment depends in part on the degree of cancer advancement in patients treated by several groups of institutions inside and outside of the NCI. True evaluation of the benefit of the NK cell treatment still remains to be defined. Toxicity assessment and study on the mode of action are also important next steps for wider clinical application. Dr. Ogawa mentioned that two groups of investigators are using this treatment with ovarian and gastric cancers in Japan. This area of study may be a subject of future discussion under the U.S.-Japan Cancer Program.
Three scientists came to the United States as Exchange Scientists under the Biology and Diagnosis Program Area. Dr. M. Sakai visited the Fox Chase Cancer Center and NIMH for studies of cloning and the regulation mechanisms of glutathione S-transferase P, immunoglobulin and ribosomal genes. Dr. M. Taniguchi visited NIAID and the Fred Hutchinson Cancer Center for collaborative studies of the functional domain of the cDNA that encodes melanoma specific antigen. Dr. T. Kishimoto visited the University of South Carolina, NIAID, and Stanford University to discuss recent progress on BSF1 and BSF2, lymphocyte surface molecules, and to participate in the International Lymphokine Workshop.
Three meetings were held in the Treatment Program Area. Dr. Ogawa reported on the seminar on “Bone Marrow Transplantation” that was held in Tokyo, November 7-8, 1986. Allogeneic BMT are effective on ALL, ANLL and lymphoma. Syngeneic transplants are effective in CML. Good results from BMT were noted in patients with the first relapse from ALL and CML. Although the problems with the toxicity, infection, late relapse, rejection and cost of treatment prohibit clearly demonstrable benefit from BMT, however, it will certainly open new ways of cancer treatment in the near future. Exchange of valuable information on BMT which is less employed in Japan than in the United States was very useful. Drs. Adamson, Hodes, and Masnyk asked about long-term relapse and risk associated with BMT treatment. Drs. Friedman and Ogawa responded that the patients who receive BMT are already exposed to a high degree of risk from their primary diseases. Improvement in their survival, clinical release and prognosis attributed from BMT is valuable, although the positive response remained limited to certain types of cancers at this moment. Further development of BMT technology and accumulation of clinical experiences in the future are highly desirable.
The seminar on “Neoadjuvant and Adjuvant Therapy” was held in Hawaii on February 3-4, 1987. Neoadjuvant therapy with chemotherapy preceding radiotherapy or surgery is being explored. Combination of chemotherapeutic agents has been evaluated. For breast cancer, higher intensity of therapy resulted in better results. 5FU+CDDP with simultaneous radiation showed significant reduction of tumors. Large scale studies on gastric and colorectal cancers in Japan were reported. Extensive neoadjuvant studies are in progress in the United States. All participants felt that a future summation of data from both countries would be very useful.
The seminar on “Biochemical Pharmacology of Treatment Failure” was held in Washington, D.C., with seven Japanese participants and a large number of United States participants from local areas. The meeting dealt with biochemical pharmacology of treatment failure, multidrug resistance, and the phenotypic and genetic mechanisms involved. This fast growing area is drawing much attention by basic and clinical researchers in the United States and Japan. Clinical relevance of drug resistance, modulation of the resistant phenotype, and supervening mechanisms of drug sensitivity and insensitivity were discussed intensively. A search for new drugs with new screening methodologies was also reported. Inhibitors of glutathione S-transferase as a reversing agent for drug resistance were introduced by Drs. Ogawa and Friedman. The meeting was evaluated as highly successful by all participants on both sides.
The outlines of the three seminars held under the auspices of the Treatment Program Area of the U.S.-Japan Cancer program have been published in “Cancer and Chemotherapy,” vol. 14, 1987.
Three scientists from Japan visited the United States as Exchange Scientists in the Treatment Program Area. Dr. T. Ohnishi visited the Department of Neoplastic Diseases, Mount Sinai School of Medicine, for the study of the current status of cancer chemotherapy in the United States. Dr. K. Aiba is currently visiting NCI for the study of biochemical modulation of antitumor drugs. Dr. K. Inoue completed a one-year study on cis-DDP adduct assay systems at NCI.
Dr. Sugano explained a principle of the Interdisciplinary Program which focused on differences between the United States and Japan in the frequency of certain cancers and to explore these differences for a new opportunity for research. A seminar on “Hepatitis B Virus and Primary Hepatocellular Carcinoma” was held in Hawaii on January 29-30, 1987. Discussed extensively in the seminar were epidemiological and pathological problems; nutritional factors; synergistic, multifactorial and multistep aspects of action by chemical carcinogen, alcohol, thorotrast and schistosomiasis; chromosomal rearrangement and deletion; PHC-related oncogene (lca); animal model systems; and viral replication. Participants believed that the new systems and techniques described at this seminar would lead to rapid progress in understanding the components of hepatocarcinogenesis in humans.
Dr. Adamson pointed out Dr. Omata’s experiment that aflatoxin can accelerate development of PHC in duck infected with DHBV may be a good model for human PHC in China and Africa. Early development of PHC in Africa may be explained by a combined effect of chemical carcinogens on HBV infection. Dr. Sugimura mentioned a previous study that indicated S9 fraction from hepatitis B infected liver showed a higher metabolic activation of aflatoxin. There may be various reasons to explain these interesting phenomena.
The seminar on “Genetics of Human Cancer” was held in Los Angeles on March 23-25, 1987. The topics of discussion included retinoblastoma which occurs in a hereditary and non-hereditary forms. The two-mutation model as well as antioncogenes were discussed by Dr. Knudson who discovered the genetic and molecular background of the disease. Deletion in Rb gene that is located on 13q14 was found not only in Rb but in other tumors as well. Hereditary components and their molecular mechanisms involved in carcinogenesis of Wilms’ tumor, colorectal cancer, xeroderma pigmentosm, ataxia telangiectasia, Blooms syndrome and Fanconi’s anemia were discussed. Multiple endocrine neoplasia and cancer families with sarcoma and other neoplasm were widely reviewed. Also discussed were epidemiology of neoplasms in the United States and Japan, atomic bomb survivors and new methodology in understanding of mechanisms in carcinogenesis. The new concept of “antioncogene” or “recessive oncogene” and a variety of new molecular methods introduced in the field of cancer research and human genetics are the outstanding highlight of this seminar. Dr. Adamson commented on the study by Bennedict who succeeded in the cloning of the Rb gene and using it as a probe for investigation of other neoplasms. The study will be published in Science. A great deal of difference in frequencies and their trends in the United States and Japan of lung, stomach, colon, prostate, esophageal and pancreatic cancers, osteosarcoma, Ewing’s sarcoma, postmenopausal breast cancer, autoimmune diseases are of particular interest for future study. Also mentioned were significant differences in subtypes and subsites of cancers in different ethnic groups in different geographic areas studied by Drs. Miller and Sugano and discussed in earlier U.S.-Japan Cancer Program. Dr. Ogawa asked the difference in follicular and nodular forms of lymphomas in Japan and Japanese-Americans in Hawaii. Dr. Sugano responded that the incidence of lymphoma in Japan and Japanese ancestors in Hawaii is low, but is increasing in non-Hodgkin’s lymphoma, while Hodgkin’s lymphoma remains at a low level. Nodular lymphoma in Japanese in Japan as well as in Hawaii is low. T cell lymphoma is restricted in southern areas of Japan.
Three scientists visited the United States as Exchange Scientists under the Interdisciplinary Program Area. Dr. Mori visited the University of Southern California, NCI, and the University of Washington for the study of cancer epidemiology and SEER program. Dr. Hino visited the Albert Einstein College of Medicine for collaborative study on HBV and PHC with Dr. Rogler. Dr. Kino visited the Armed Forces Institute of Pathology, the University of Minnesota Hospital, and the Beth Israel Hospital in Boston for investigating subtype and subsite differences of stomach cancers in the United States and Japan. A significant difference in the location and histological types was observed.

FUTURE PLANS

Twelve future seminars or symposia are envisioned, nine in the United States and three in Japan. Fifteen scientists will be in the Exchange Scientist Program, fourteen from Japan, and one from the United States, Mutagenic heterocyclic amines will be sent from Japan to the U.S. Carcinogen Depository and made available for use by the United States scientists. Fecapentaene will be sent to the National Cancer Center of Japan for its carcinogenesis study.

Planned Seminars in the Etiology Program Area for FY 87:
1. Cancer Cell Membrane: Aberrant Glycosylation and Other Critical Molecular Events, March 1988, in Hawaii.
2. Glutathione S-transferases and Chemical Hepatocarcinogenesis. March 1988, in Hawaii.
3. Development of New Medium-term Bioassay for Carcinogenesis. December 1987, in Hawaii.
4. Biology of Oncogene. March 1988, in Hawaii.

Planned Seminars in the Biology and Diagnosis Program Area:
1. Molecular Biology of Cancer Cells. March 1988, in Kyoto.
2. Molecular Mechanisms of Lymphoid Cell Interaction and Application to Tumor-immunology. January 1988, in Hawaii.
3. Molecular Diagnosis of Cancer. January 1988, in Hawaii.

Planned Seminars in the Treatment Program Area:
l. The Role of Cytokines in Cancer Treatment. November 1987, in Tokyo.
2. New Screening Systems and New Drugs. February 1988, in Hawaii.
3. Current Progress of Combined Modality of Radiotherapy and Chemotherapy. March 1988, in San Francisco.

Planned Seminars in the Interdisciplinary Program Area:
1. Melanoma and Skin Cancer: Biology and Comparative Features in the United States and Japan. November 1987, in Tokyo.
2. Familial Cancer. March 21-23 1988, in Hawaii.


Proposed Exchange Scientists