Mutagenesis Advance Access originally published online on May 13, 2008
Mutagenesis 2008 23(5):341-346; doi:10.1093/mutage/gen018
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Survival and tumorigenesis in O6-methylguanine DNA methyltransferase-deficient mice following cyclophosphamide exposure
Department of Pediatrics 1Committee on Cancer Biology 2Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA 3Biological Engineering Division and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 4Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA
O6-methylguanine DNA methyltransferase (MGMT) deficiency is associated with an increased susceptibility to alkylating agent toxicity. To understand the contribution of MGMT in protecting against cyclophosphamide (CP)-induced toxicity, mutagenesis and tumorigenesis, we compared the biological effects of this agent in transgenic Mgmt knockout and wild-type mice. In addition, neurofibromin (Nf1)+/– background was used to increase the likelihood of CP-induced tumorigenesis. Cohorts of Mgmt-proficient or -deficient mice (either Nf1+/+ or Nf1+/–) were given 6 weekly injections of a maximally tolerated dose of CP (250 mg/kg) or vehicle and followed for 15 months. CP-treated mice had more deaths than control mice but there was no difference in the long-term survival between Mgmt+/+ and Mgmt–/– mice (12 of 83 Mgmt+/+ mice died compared to 12 of 80 Mgmt–/– mice, disregarding Nf1 status). Lymphomas and adrenal tumours were the most frequent malignancies. Interestingly, CP-treated, Mgmt-deficient mice developed fewer tumours than controls. Ten of 71 (14%) Mgmt-proficient mice developed tumours after CP treatment compared to only 2 of 68 (3%) Mgmt-deficient mice (P = 0.02). Mgmt–/–, Nf1+/– mice developed fewer tumours (1 of 35, 3%) following CP compared to Mgmt+/+, Nf1+/– mice (7 of 37, 19%) (P = 0.03). Hypoxanthine–guanine phosphoribosyltransferase mutation assays showed no significant increases in mutant frequencies in Mgmt–/– (18.1 x 106) compared to Mgmt+/+ mice (12.9 x 106). These data indicate that MGMT deficiency does not protect against long-term toxicity or mutagenicity from CP and appears to attenuate the occurrence of CP-induced tumours in an Nf1+/– background.
* To whom correspondence should be addressed. Tel: +1 773 702 4441; Fax: +1 773 702 3002; Email: edolan{at}medicine.bsd.uchicago.edu
Both the authors contributed equally to this work.
Received on March 19, 2007; revised on February 27, 2008; accepted on March 21, 2008.