Role of deoxynucleoside triphosphate pools in the cytotoxic and mutagenic effects of DNA alkylating agents.

The objective of these studies was to define the role of deoxynucleoside triphosphate pools in the cytotoxic and mutagenic effects of DNA alkylating agents. Survival of Chinese hamster ovary (CHO) cells after treatment with DNA alkylating agents was clearly related to the balance of the dCTP and dTTP pools--high dCTP/dTTP ratios increased the survival of CHO cells 2- to 10-fold compared to treatment in low dCTP/dTTP. Induction of mutations at three genetic loci by one agent, ethyl methane sulfonate (EtMes) was also affected by pool alterations. Although the maximum mutagenesis obtained in high or low dCTP/dTTP was not significantly different, it took considerably lower concentrations of EtMes to obtain this maximum in conditions giving low dCTP/dTTP. These results are consistent with a common mechanism: mispairing of thymine with the O6-alkylated guanine--causing both the cytotoxic and mutagenic effects of EtMes. They also suggest that alterations of dCTP/dTTP ratio may be involved in certain human genetic diseases characterized by increased sensitivity to DNA alkylating agents.