| 17116724 |
Hansen RJ, Nagasubramanian R, Delaney SM, Samson LD, Dolan ME: Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice. Carcinogenesis. 2007 May;28(5):1111-6. Epub 2006 Nov 20.
The DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) protects from toxicity and mutations incurred following alkylating agents by removing O (6)-alkylguanine lesions. Using Mgmt-/- mice, we examined MGMT's role in protecting from in vivo mutations induced by three different alkylating agents, temozolomide (TMZ), 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide. Mutant frequencies were determined in the hypoxanthine-guanine phosphoribosyltransferase gene of splenic T-lymphocytes from C57BL/6 mice (Mgmt+/+ and Mgmt-/-) following TMZ, BCNU or cyclophosphamide. Following TMZ, the mutation frequency was significantly greater in Mgmt-/- mice (5.5 and 9.8 x 10 (-6) for 7 and 10 mg/kg TMZ, respectively) compared with vehicle-treated mice (1.0 x 10 (-6), P BCNU (7.5 mg/kg) was the same regardless of Mgmt status. Similarly, pretreatment of Mgmt+/+ mice with 30 mg/kg O (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 x 10 (-6) in control-treated mice to 12.9 x 10 (-6) in Mgmt+/+ and 18.1 x 10 (-6) in Mgmt-/- mice, although the difference in Mgmt-/- compared with Mgmt+/+ was not significant. Acrolein and chloroacetaldehyde, metabolites of cyclophosphamide, were not mutagenic in Mgmt+/+ and Mgmt-/- mice. These results demonstrate that MGMT significantly protects against in vivo TMZ-induced mutations and that MGMT deficiency does not result in greater mutation frequency following cyclophosphamide or BCNU compared with wild-type mice. |
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