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The DNA repair proteinO  6-methylguanine-DNA methyltransferase (MGMT) protects from toxicity and mutations incurred following alkylating agents by removingO  6-alkylguanine lesions. UsingMgmt−/− mice, we examined MGMT's role in protecting fromin vivomutations induced by three different alkylating agents, temozolomide (TMZ), 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide. Mutant frequencies were determined in thehypoxanthine–guanine phosphoribosyltransferasegene of splenic T-lymphocytes from C57BL/6 mice (Mgmt+/+ andMgmt−/−) following TMZ, BCNU or cyclophosphamide. Following TMZ, the mutation frequency was significantly greater inMgmt−/− mice (5.5 and 9.8 × 10−6for 7 and 10 mg/kg TMZ, respectively) compared with vehicle-treated mice (1.0 × 10−6,P≤ 0.05). In contrast, TMZ-induced mutations were not increased over vehicle inMgmt+/+ mice. The mutation frequency of mice treated with BCNU (7.5 mg/kg) was the same regardless ofMgmtstatus. Similarly, pretreatment ofMgmt+/+ mice with 30 mg/kgO  6-benzylguanine, a potent inactivator of MGMT, prior to BCNU (15 mg/kg) did not result in significantly more mutations than mice treated with BCNU alone. Following cyclophosphamide, mutation frequencies significantly increased from 1.8 × 10−6in control-treated mice to 12.9 × 10−6inMgmt+/+ and 18.1 × 10−6inMgmt−/− mice, although the difference inMgmt−/− compared withMgmt+/+ was not significant. Acrolein and chloroacetaldehyde, metabolites of cyclophosphamide, were not mutagenic inMgmt+/+ andMgmt−/− mice. These results demonstrate that MGMT significantly protects againstin vivoTMZ-induced mutations and that MGMT deficiency does not result in greater mutation frequency following cyclophosphamide or BCNU compared with wild-type mice.

carcinogenesis

Role of               O  6              -methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice