Journal Article

Role of <i>O</i><sup>6</sup>-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice

Ryan J. Hansen, Ramamoorthy Nagasubramanian, Shannon M. Delaney, Leona D. Samson and M.Eileen Dolan

in Carcinogenesis

Volume 28, issue 5, pages 1111-1116
Published in print May 2007 | ISSN: 0143-3334
Published online November 2006 | e-ISSN: 1460-2180 | DOI:
Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice

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The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) protects from toxicity and mutations incurred following alkylating agents by removing O6-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 × 10−6 for 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 in Mgmt+/+ mice. The mutation frequency of mice treated with BCNU (7.5 mg/kg) was the same regardless of Mgmt status. Similarly, pretreatment of Mgmt+/+ mice with 30 mg/kg O6-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 × 10−6 in control-treated mice to 12.9 × 10−6 in Mgmt+/+ and 18.1 × 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.

Journal Article.  4263 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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