SUMMARY OF ACTIVITIES

The year April 1, 1980 to March 31, 1981 constitutes the second year of the second Five-Year Program of the U.S.-Japan Cooperative Cancer Research Program. The major objective of the Etiology Area of the Program is to identify carcinogenic factors and clarify mechanisms of carcinogenesis with a view to providing a fundamental basis for understanding the causation of human cancer.
Epidemiologic studies have provided persuasive evidence that a majority of human cancer cases are caused by environmental (i.e., exogenous) rather than endogenous factors. This is an optimistic message since it means that if we could identify the exogenous causative factors we could hope to prevent a majority of human cancer cases, either by reducing human exposure or protecting the host. Significant progress has already been made through the identification of cigarette smoking as the major cause of lung cancer. In addition, over 20 chemicals or chemical processes have been implicated in various forms of human cancer. However, the specific causes of other prevalent cancers (i.e., cancers of the stomach, large bowel, breast, and prostate) have not been identified with certainty. In addition, several important general questions remain unresolved. These include the current controversies concerning the extent to which human cancers are caused by naturally occuring versus man-made chemicals, the relative contribution of initiators and promoters, the role of chemical versus viral agents, the role of general nutritional factors (i.e., fat, fiber, and vitamins), and the role of multifactor interactions.
The Etiology Program Area of the U.S.-Japan Cooperative Cancer Research Program includes four sub-areas: Epidemiology, Chemical Carcinogenesis, Viral Carcinogenesis, and Genetics, thus reflecting the importance of considering all four of these diverse subjects in the origin of human cancers. The interdisciplinary seminars and the Exchange Scientist Programs held during the past year under the auspices of the Etiology Program Area reflect this
multidisciplinary emphasis.
For example, the seminar entitled "Biochemical Epidemiology" held in Honolulu in February 1981 brought epidemiologists together with laboratory scientists (from the fields of chemical carcinogenesis, cytogenetics, and analytical chemistry) to discuss novel approaches that combine laboratory methods with epidemiologic techniques. The seminar entitled "Interspecies Correlations in Chemical Carcinogenesis" held in Tokyo in March 1981 addressed topics that are fundamental to understanding the difficult problems encountered in extrapolating results obtained from animal bioassays or in vitro assays of humans. With the recent intensification of worldwide efforts in the area of carcinogen bioassays and cancer epidemiology, the problem of risk extrapolation has become acute. The "Interspecies" seminar provided a useful summary of current knowledge and unresolved problems related to this important area. The content of these two seminars is discussed in greater detail later in this report.
During the past year the Etiology Program Area had eight exchange scientists representing the disciplines of cancer epidemiology and biostatistics, tumor virology, and chemical carcinogenesis. As in the past, the Exchange Scientist Program was extremely fruitful in fostering the exchange of recent, often unpublished, information between United States and Japanese scientists. In addition, it stimulated novel collaborative research projects which would not otherwise have been possible. Detailed reports are given in the following sections of these Proceedings, but a few of the highlights are cited here. There were two exchange scientists in the area of epidemiology and biostatistics. One project related to biostatistical techniques as they apply to carcinogen bioassays and the difficult problem of extrapolations of potency from short term mutagenesis assays. The other was concerned with the epidemiology of two prevalent human diseases, namely lung and prostate cancer. Recent advances in tumor virology combined with powerful new molecular genetic techniques (restriction enzyne analysis, recombinant DNA methods, and gene cloning) are providing important insights into the carcinogenic process at the molecular level. Three exchange scientists carried out related projects in these areas. These projects led to important advances in liposome-mediated techniques for enhancing the uptake of DNA and other macromolecules by mammalian cells, the construction of SV40 DNAs carrying specific deletions, and the cloning of a specific fragment of DNA related to the mechanism by which an adenovirus DNA (CELO virus) undergoes amplification in host cells during cell transformation and tumor progression. Another Exchange Scientist Program led to the isolationand purification of the compound Lyngbyatoxin from a blue-green algae native to Hawaii. This unusual indole alkaloid is structurally related to a highly potent class of tumor promoters recently discovered by Dr. Takashi Sugimura and his colleagues. Sufficient amounts of this compound were obtained for definitive assays for tumor promotion in mice and for studies on mechanism of action in cell culture systems. The latter studies will contribute to our understanding of the multistage carcinogenic process.