DNA repair as regulatory factor in the organotropy of alkylating carcinogens

Abstract

Monofunctional alkylating agents which react predominantly at nitrogen atoms in DNA bases (e.g. alkyl methanesulphonates, dialkylsulfates) are generally weak carcinogens whereas compounds which lead extensively to oxygen alkylation (e.g. alkylnitrosoureas, dialkylnitrosamines, dialkyl-aryltriazenes) often exhibit a strong carcinogenic activity. O6-Alkylation of guanine is a pro-mutagenic DNA modification possibly involved in the initiation of malignant transformation. O6-Alkylguanine can be enzymically excised and in the rat the induction of neural, renal and colonic tumors by alkylnitrosoureas, 3,3-dimethyl-1-phenyltriazene, dimethylnitrosamine and 1,2-dimethylhydrazine correlates with an excision repair deficiency in the target tissue. However, species and strain differences in the response to these carcinogens are not paralleled by differences in the excision repair capacity for O6-alkylguanine. Preliminary data suggest that in rat liver there is an inducible enzyme system for the removal of O6-alkylguanine from DNA.