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Carcinogenesis Advance Access published online on November 20, 2006
Carcinogenesis, doi:10.1093/carcin/bgl218
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 24, 2006
Revised October 24, 2006
Accepted November 4, 2006

CARCINOGENESIS

Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice

Ryan J. Hansen 1, Ramamoorthy Nagasubramanian 2, Shannon M. Delaney 3, Leona D. Samson 4, and M. Eileen Dolan 5 *

1 Committee on Cancer Biology, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637
2 Department of Pediatrics, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637
3 Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637
4 Biological Engineering Division and Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
5 Committee on Cancer Biology, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637; Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637; Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637

* To whom correspondence should be addressed.
M. Eileen Dolan, E-mail: edolan{at}medicine.bsd.uchicago.edu


  Abstract

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), BCNU and cyclophosphamide. Mutant frequencies were determined in the Hprt 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 to 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 - 10-6 in Mgmt-/- mice, although the difference in Mgmt-/- compared to 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 to wild type mice.

Keywords: MGMT; mice; Hprt mutations; temozolomide; BCNU; cyclophosphamide; acrolein; chloroacetaldehyde.
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