Carcinogenesis Advance Access originally published online on November 20, 2006
Carcinogenesis 2007 28(5):1111-1116; doi:10.1093/carcin/bgl218
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Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice
Committee on Cancer Biology
1 Department of Pediatrics
2 Department of Medicine and
3 Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
4 Biological Engineering Division and Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
* To whom correspondence should be addressed. Tel: +1 773 702 4441; Fax: +1 773 702 0963;Email: edolan{at}medicine.bsd.uchicago.edu
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 x 10–6 for 7 and 10 mg/kg TMZ, respectively) compared with vehicle-treated mice (1.0 x 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 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.
Abbreviations: BCNU (carmustine), 1,3-bis (2-chloroethyl)-1-nitrosourea; BG, O6-benzylguanine; CAA, chloroacetaldehyde; Hprt, hypoxanthine–guanine phosphoribosyltransferase; MGMT, O6-methylguanine-DNA methyltransferase; TMZ, temozolomide
Received October 24, 2006; revised October 24, 2006; accepted November 4, 2006.
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