Mechanisms of chemical carcinogenesis.

Of the known carcinogenic agents (viruses, ultraviolet and ionizing radiations, and chemicals), chemicals appear to be of major importance in the induction of human cancers. The known chemical carcinogens include a wide range of structures. Their common feature is that their ultimate forms are electrophilic reactants; in most cases, these reactants arise through metabolism in vivo. Carcinogenesis by chemicals is a multistage process. The first stage, initiation, occurs rapidly and appears to be irreversible. The available data indicate that initiation generally results from one or more mutations of cellular DNA. Covalent reactions of electrophilic derivatives of carcinogens with DNA are the major cause of these mutations. The second stage, promotion, occurs over a longer period of time. Promotion is a complex process, for which the early stages are largely reversible. The critical events appear to be epigenetic. Complete carcinogens have both initiating and promoting activities, but the ratios of these two activities for various chemicals may differ greatly. This knowledge of the mechanisms of carcinogens by chemicals provides a useful basis for approaches to the prevention of human cancer.