Survival and tumorigenesis in O6-methylguanine DNA methyltransferase-deficient mice following cyclophosphamide exposure

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...

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Published in:Mutagenesis 2008-09, Vol.23 (5), p.341-346
Main Authors: Nagasubramanian, Ramamoorthy, Hansen, Ryan J., Delaney, Shannon M., Cherian, Mathew M., Samson, Leona D., Kogan, Scott C., Dolan, M. Eileen
Format: Article
Language:English
Subjects:
Alkylating Agents - toxicity
Animals
Cell Transformation, Neoplastic - chemically induced
Cell Transformation, Neoplastic - genetics
Cyclophosphamide - toxicity
Hematopoiesis - drug effects
Hypoxanthine Phosphoribosyltransferase - genetics
Mice
Mice, Knockout
Mutagenesis
Mutation
Neurofibromin 1 - genetics
O-Methylguanine-DNA Methyltransferase - genetics
O-Methylguanine-DNA Methyltransferase - physiology
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Summary: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 × 106) compared to Mgmt+/+ mice (12.9 × 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.
ISSN:0267-8357
1464-3804
DOI:10.1093/mutage/gen018