Carcinogenic Alkylating Agents*

Abstract

Cells are continuously exposed to large numbers of alkylating agents, from both exogenous and endogenous sources, which result in the formation of DNA adducts. Efficient DNA repair processes may restore damaged DNA. Unrepaired DNA adducts, however, can initiate the neoplastic process by inducing mutations and altering the expression of critical genes. Similar mechanisms are responsible for the progression from benign to malignant to metastatic neoplasia. In many cases, the formation and persistence of DNA adducts correlate with carcinogenic potency. However, different DNA adducts vary in their potential for initiating carcinogenesis, and their toxicological relevance must also be considered. The significance of individual adducts can be determined by molecular biology techniques, such as site-directed mutagenesis. Information on relevance, together with that of DNA adduct formation and DNA repair, is useful in estimating risk from exposure to exogenous alkylating agents. Recent evidence indicates that significant DNA alkylation arises from endogenous sources, and may be important in aging and spontaneous carcinogenesis. The relative risk from endogenous DNA alkylating agents merits consideration when evaluating risk from exogenous sources.