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Kunie Yoshikawa

Life Science Research Sector, Yokohama Research Center, Mitsubishi Chemical Corporation, Yokohama 227, Japan

Abstract
According to current data, the capacity to cause nonprogrammed or unscheduled cell proliferation in target tissues, a common characteristic of chemical carcinogens, may play a more important role in the development of tumors than does genotoxicity. This paper provides strong support for the validity of this conclusion. Ames-negative nongenotoxicants may be considered to be carcinogenic primarily because of their ability to induce cell proliferation in animal tissues and organs. In addition, such nongenotoxic carcinogens may also provide latent and modest DNA (equivocal) modifications that never lead to Ames-positive events. Conversely, noncarcinogenesis by Ames-positive agents is likely to be linked to a lack of stimulation of cell division. Nongenotoxic and genotoxic carcinogens rely on both cell proliferation and equivocal DNA modification for their full carcinogenicity. Such equivocal DNA modifications do not appear to be formed by tumor promoters. The role of cell proliferation may provide a favorable milieu for the occurrence of genetic instability, give rise to selective "apoptosis-resistant abnormal cells," and then affect clonal expansion of these cells. Therefore, understanding the influence of nongenotoxic and genotoxic carcinogens on cell proliferation capability is a key point in determining the mechanisms of chemical carcinogenesis. Considering the contradictory and common features of genotoxicants and carcinogens, early detection of nonprogrammed cell proliferation is the most effective approach to predict human and rodent carcinogenicity. Key words: Ames test, carcinogen, cell proliferation, genotoxic, hepatocarcinogen, 8-hydroxydeoxyguanosine, noncarcinogen, nongenotoxic, tumor promoters. Environ Health Perspect 104:40-46 (1996)