Survival and tumorigenesis in O6-methylguanine DNA methyltransferase-deficient mice following cyclophosphamide exposure.
O(6)-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 10(6)) compared to Mgmt+/+ mice (12.9 x 10(6)). 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.
Nagasubramanian
Ramamoorthy
R
Department of Pediatrics, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Hansen
Ryan J
RJ
Delaney
Shannon M
SM
Cherian
Mathew M
MM
Samson
Leona D
LD
Kogan
Scott C
SC
Dolan
M Eileen
ME
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics; D003520:Cyclophosphamide / Q000633:toxicity*; D006410:Hematopoiesis / Q000187:drug effects; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000502:physiology*
D000477:Alkylating Agents; D025542:Neurofibromin 1; D003520:Cyclophosphamide; D019853:O(6)-Methylguanine-DNA Methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase