PROGRAM AREA REPORTS

CHEMICAL CARCINOGENESIS PROGRAM

The activities of the Chemical Carcinogenesis Program Area include, for the most part, the conferences, exchange of scientists, and exchange of resources. In each of these activities, the results have been mutually productive for both Japan and the United States.

CONFERENCE ACTIVITIES

The joint conferences have covered several different areas of chemical carcinogenesis to encourage participation of more scientists, including such topics as carcinogenicity testing in animals, cellular and molecular control in neoplasia, carcinogenesis by polycyclic hydrocarbons, and DNA repair and misrepair in chemical and radiation carcinogenesis. The multidisciplinary planning of the conferences has been based on a policy of utilizing binational seminars agreed upon between the coordinators. The coordinators state that the program has been necessarily broad in scope because of the breadth and complexity of the field of chemical carcinogenesis, the diversity of compounds and mechanisms of action, the need to investigate the process at each of several levels of biological organization and at successive stages in the evolution of neoplasia, the emergence of new techniques for evaluating transformation in cultured cells, and the urgent need to develop and exploit improved methods for the detection of carcinogenic chemicals. Nevertheless, it cannot be expected that optimal progress will be made in this field without adequate coverage of its various developing subject areas. Some of the seminars were sponsored jointly by the Chemical Carcinogenesis Program and other programs such as those within the National Science Foundation (NSF), or were held on the occasion of other international symposiums. This flexibility saved expenses and increased participation of scientists when needed.
The “Seminar on Evaluation of Experimental Methods of Carcinogenicity Testing in Animals” was held November 17-19, 1975, at Hakone, with eight American scientists and 30 Japanese scientists participating. Detailed discussions during the seminar helped to coordinate the efforts of both countries in this difficult, timely, and costly activity.
The “Symposium on Modified Cellular and Molecular Controls of Neoplasia” was sponsored jointly by the Chemical Carcinogenesis Program and the U.S.-Australian Agreement for Cooperation in Science (NSF) on December 9-12, 1975, in Honolulu, with seven Australian scientists, nine Japanese scientists, and 26 American scientists. In the area of cell regulation, the exchange of information in this rapidly advancing field will greatly enhance the effectiveness of related research in the U.S. as well as in Japan. The proceedings of the symposium were published by Raven Press under the title Control Mechanisms in Cancer.
The “Conference on Aromatic Polycyclic Hydrocarbons” was held on January 23-26, 1977, in New Orleans. The purpose of this conference was to develop a discussion in which various aspects related to polycyclic hydrocarbons would be covered. Many individuals who ordinarily do not interact with one another were brought together to discuss the following general subjects: chemistry, metabolism, enzymology, macromolecule interaction, DNA repair, in vitro transformation, animal models and lung cancer, tobacco carcinogenesis, biology, energy sources, environmental monitoring, and epidemiology. The main thrust of the conference was on Benzo[a]pyrene and the areas developed were: (1) new aspects of chemical synthesis of metabolites; (2) activation and detoxification of Benzo[a]pyrene; (3) interaction of the active metabolite with DNA and its structure elucidation; (4) the mutagenic and transformation activity of the metabolites; (5) the role of DNA repair of the DNA-bound metabolite; (6) the genetics of laboratory animals and humans in the activation and detoxification systems; (7) the enzymatic basis for activation and detoxification; (8) the impact of new energy sources on polycyclic hydrocarbons in the environment; (9) the monitoring of polycyclic hydrocarbons in the environment; (10) the role of polycyclic hydrocarbons in tobacco carcinogenesis; and (11) epidemiological studies on the role of polycyclic aromatic hydrocarbons in human cancer.
Within the framework of the above subjects, 45 papers were presented by scientists from the United States and Japan, as well as by several scientists from France and England. The meeting was most useful because the dissemination of information from different areas of research was unusually high. In evaluating the conference, the coordinators stated that “For the first time, scientists from many disciplines have met together to confront one common problem: polycyclic hydrocarbon carcinogenesis.” Proceedings of this conference are being prepared for publication in the near future.
The “Seminar on the Role of DNA Repair and Misrepair in Radiation and Chemical Carcinogenesis” was held in Kyoto on December 12-14, 1977, with seven American participants, thirteen Japanese, and two British scientists. Emphasis was placed on molecular analysis of correlation between DNA misrepair and mutation or cancerization. Some interesting data included: high incidence of cancer in those patients with inheritable DNA repairing deficiency; some factors including some enzymes, readily influenced by cell cycles and modes of chemical binding DNA, control mutation rates; differences of DNA repairing systems between prokaryotes and eukaryotes, supporting difficulty in proving the involvement of DNA misrepair in cell mutation; and further elucidation of the correlation between forms of DNA misrepair and cancerization.
The meetings that were held during this period of review were thus highly valuable in bringing together the relevant scientists from both countries for in-depth exchange of information and promising new approaches.
Future plans include a seminar on the role of host factors on carcinogenesis, being planned for December 1978, aiming to clarify mechanisms of some tumor-promoting agents.

EXCHANGE OF SCIENTISTS

The program for the exchange of scientists was in most cases used to acquire or exchange specific techniques or information in the most urgent subareas. Two exchange visitors contributed greatly to exchange techniques for carcinogen testing.
One exchange visitor, an American scientist, transferred techniques of bacterial mutagenicity assay for carcinogen testing, and formed mutagenic activity in 84 percent of the shampoo-type hair dyes, and 59 percent of the oxidative powder-type hair dyes. The scientist learned in detail certain modifications and refinements in methodology that had been developed in Japan, including a test for DNA repair. Techniques were also learned for isolating mutagenic metabolities of hair dyes formed in vivo.
Another exchange visitor, a Japanese scientist, returned to his country from the United States with a technique for testing carcinogens by a cell culture system. A scientific group has been formed under this subject within the Special Cancer Grant System under the Ministry of Education, Science, and Culture of Japan.
Other notable accomplishments by the exchange scientists include: a Japanese scientist conducted collaborative research at the NCI to further the elucidation of Benzo[a]pyrene derivative-glutathione-S-transferase, a key enzyme for inactivation of active carcinogen metabolite; an American pathologist conducted collaborative histopathological research on nitrosourea-induced leukemias in rats and on human and animal hepatocellular carcinomas at the National Institute of Hygienic Sciences; and an American scientist brought to the Institute of Medical Science, University of Tokyo, Chinese hamster ovary cells, which were very suitable for the study of mammalian cell mutation, serving as an appropriate system to screen environmental mutagens and comutagens.
In general, the exchange of American and Japanese scientists proved complementary and very productive. Prior arrangements between the visitors and the host institutions proved to be crucial, particularly in achieving fruitful results for short visits. Visiting several different laboratories during a short trip was not of significant benefit in this program area.

EXCHANGE OF RESOURCES AND MATERIALS

In the area of resources and materials exchange, an ad hoc committee was formed to oversee the U.S. distribution of protease inhibitors donated the previous month by the Japan Society for the Promotion of Science (JSPS). These inhibitors, unavailable commerically, consisted of antipain (700 g), glucanolactum (600 g), Ieupeptin (700 g), and pepstatin (400 g). Thus the protease inhibitors supplied by the JSPS have enabled U.S. cancer investigators to carry out certain explorations that would not otherwise have been possible. Because of the fundamental implications and promise of these studies, this program accomplishment deserves recognition.
An announcement of the availability of the compounds has been submitted for publication in Cancer Research and in the Journal of the National Cancer Institute. Because of this announcement, and influences by a joint seminar on protease inhibitors held in the previous year within this program area, requests for protease inhibitors by American scientists have accelerated, resulting in an additional shipment of chymostatin (200 g), elastatinal (200 g), and phosphoramidon (50 g). These protease inhibitors have been extremely useful to U.S. investigators. A particularly noteworthy outcome is the recent publication of a report (Proceedings of the National Academy of Science 74(3): 1152-6, March 1977) demonstrating the inhibition, by antipain, of UV-induced mutagenesis in E. coli. This result, implying that the process of mutagenesis may be counteracted by appropriate metabolic intervention has far-reaching implications for studies in the biology of mutation and tumor initiation. Since the publication of this report, requests for antipain and other protease inhibitors have increased appreciably in number.