Oncogenesis, Mutagenesis, DNA Damage, and Cytotoxicity in Cultured Mammalian Cells Treated with Alkylating Agents¹

Mutation to 8-azaguanine resistance in Chinese hamster cells and cytotoxicity and production and repair of alkalilabile lesions in the DNA of Chinese hamster V79 and transformable mouse embryo C3H/10T$$1\over2$$ fibroblasts were measured after the cells had been treated for 2 hr with the monofunctional alkylating agents, N-methyl-, and N-ethyl-N′-nitro-N-nitrosoguanidine and methyl and ethyl methanesulfonates. In both cell lines, methylating agents were more cytotoxic than were equimolar concentrations of ethylating agents, and N-methyl- and N-ethyl-N′-nitro-N-nitrosoguanidine were more cytotoxic than were methyl methanesulfonate, and ethyl methanesulfonate. At equitoxic concentrations, N-methyl-N′-nitro-N-nitrosoguanidine was 14 times as mutagenic as was methyl methansulfonate and produced 400 times as many alkali-labile lesions; while N-ethyl-N′-nitro-N-nitrosoguanidine and ethyl methanesulfonate produced similar numbers of alkali-labile lesions and were equally mutagenic. A plot of alkali-labile lesions versus mutations was a straight line, but the frequency of alkali-labile lesions was 7 orders of magnitude greater than was the frequency of mutations; the rate of repair of the alkalilabile lesions varied inversely as the first power of the number of lesions. These findings suggest that mutagenic and alkali-labile lesions are associated but not identical and that neither lesion is associated with cytotoxicity. The results are discussed in the light of chemical theories of alkylation and mutagenesis and are compared with previous studies that showed that oncogenic and alkali-labile lesions are not uniformly associated.