Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase

Abstract

O6-methylguanine-DNA methyltransferase plays vital roles in preventing induction of mutations and cancer as well as cell death related to alkylating agents. Mice defective in the Mgmt gene, encoding the methyltransferase, were used to evaluate cell death-inducing and tumorigenic activities of therapeutic agents which have alkylation potential. Mgmt(-/-) mice were considerably more sensitive to dacarbazine, a monofunctional triazene, than were wild-type mice, in terms of survival. When dacarbazine was administered i.p. to 6-week-old mice and survival at 30 days was enumerated, LD50 values of Mgmt(-/-) and Mgmt(+/+) mice were 20 and 450 mg/kg body wt, respectively. Increased sensitivity of Mgmt(-/-) mice to 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), a bifunctional nitrosourea, was also noted. On the other hand, there was no difference in survival of Mgmt(+/+) and Mgmt(-/-) mice exposed to cyclophosphamide, a bifunctional nitrogen mustard. It appears that dacarbazine and ACNU produce O6-alkylguanine as a major toxic lesion, while cyclophosphamide yields other types of modifications in DNA which are not subjected to the action of the methyl-transferase. transferase. Mgmt(-/-) mice seem to be less refractory to the tumor-inducing effect of dacarbazine than are Mgmt(+/+) mice. Thus, the level of O6-methylguanine-DNA methyl-transferase activity is an important factor when determining susceptibility to drugs with the potential for alkylation.