Comparison of alkylating agent and radiation carcinogenesis: some aspects of the possible involvement of effects on DNA

A series of alkylating agents was classified in terms of increasing relative ability to react at O-atom sites in DNA, MMS < EMS < MNUA < ENUA. This is the order of increasing ability to induce reversion mutations, probably GC yields AT transitions, in phage T4, which could accord with the concept that O6-alkylguanines are directly miscoding bases. This series of agents was also used in a study of comparative carcinogenicity with respect to induction of thymic lymphoma in mice, a system in which x-irradiation yields tumors. A positive correlation between ability of agents to alkylate O-6 of guanine in DNA of thymus and carcinogenic potency was found. Although MMS was not active in this system, it was noted that it can induce tumors in other systems. The relationship between repair of alkylation and radiation induced damage in DNA was briefly discussed. The methylating agents induce single-strand breaks in DNA, and the principal repair system appears to fall into the category of short repair as denoted by Regan and Setlow (1974). These single-strand breaks may result from spontaneous hydrolytic depurinations of 3- and 7-methylpurines, or from enzymatic depurinations, e.g., of 3-alkyladenine and O6-alkylguanine. Aralkylating agents, which are also carcinogens, can evoke an alternative repair response of the uvr type