Carcinogenesis, Vol. 20, No. 9, 1667-1673,
September 1999
© 1999 Oxford University Press
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Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesis
Division of Hematology/Oncology and the Ireland Cancer Center, Case Western Reserve University, Cleveland, OH 44106-4937, USA
Mice deficient in the DNA mismatch repair (MMR) gene, PMS2, develop spontaneous thymic lymphomas and sarcomas. We have previously shown that PMS2–/– mice were hypersensitive to a single i.p. injection of 50 mg/kg of N-methyl-N-nitrosourea (MNU) for thymic lymphoma induction. We postulated that MNU sensitivity was due to formation of O6-methylguanine (O6-mG), which, if unrepaired by O6-alkylguanine DNA alkyltransferase (AGT), leads to apoptosis in MMR competent cells and O6-mG:T mismatches in MMR deficient cells. Tumor induction is less in MMR+/+ mice because cells with residual DNA adducts die, whereas mutagenized cells survive in MMR–/– mice. Overexpression of AGT (encoded by the methylguanine DNA methyltransferase—MGMT—gene) is known to block MNU induced tumorigenesis in mice with functional MMR. To further determine the sensitivity of PMS2–/– mice to MNU and the protective effect of hAGT overexpression, a low dose of MNU (25 mg/kg) was studied in PMS2–/– mice and PMS2–/–/hMGMT+ mice. No thymic lymphomas were found in MNU-treated PMS2+/+ and PMS2+/– mice. At 1 year, 46% of the MNU-treated PMS2–/– mice developed thymic lymphoma, compared with an incidence of 25% in both untreated PMS2–/– mice and MNU treated PMS2–/–/hMGMT+ mice. In addition, a significantly shorter latency in the onset of thymic lymphomas was seen in MNU-treated PMS2–/– mice. K-ras mutations were detected almost equally in the thymic lymphomas induced by MNU in both PMS2–/– and PMS2–/–/hMGMT+ mice, but not in the spontaneous lymphomas. These data suggest that PMS–/– mice are hypersensitive to MNU, that there are different pathways responsible for spontaneous and MNU induced thymic lymphomas in PMS2–/– mice, and that overexpression of hMGMT protects the mice by blocking non-K-ras pathways.
Abbreviations: AGT, O6-alkylguanine DNA alkyltransferase protein; MGMT, methylguanine DNA methyltransferase gene; MMR, mismatch repair; MNU, N-methyl-N-nitrosourea.
1 To whom correspondence should be addressed Email: slg5{at}po.cwru.edu..
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