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Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-82 [K. S., A. S., T. T., M. S.]; Department of Pathology, Faculty of Medicine, The University of Tokyo, Tokyo 113 [S. S., T. I.]; and Department of Biology, Fukuoka Dental College, Fukuoka 814-01 [M. S.], Japan
Gene targeting was used to obtain mice defective in the MGMT gene, encoding O6-methylguanine-DNA methyltransferase [Tsuzuki et al., Carcinogenesis (Lond.), 17: 1215–1220, 1996]. These MGMT-/- mice were most sensitive to the alkylating carcinogen, methylnitrosourea; when varied doses of methylnitrosourea were administered to 6-week-old mice and survivals at the 30th day were determined, LD50s of MGMT-/- and MGMT+/+ mice were 20 and 240 mg/kg of body weight, respectively. MGMT+/- mice were as resistant as MGMT+/+ mice, but some difference in survival time was noted when the two genotypes of mice were exposed to a relatively high dose of methylnitrosourea. A large number of thymic lymphomas, as well as lung adenomas, occurred in MGMT-/- mice exposed to methylnitrosourea at a dose of 2.5 mg/kg of body weight. In case of exposure to the same dose of drug, no or few tumors occurred in the MGMT+/+ and MGMT+/- mice. It appears that the DNA repair methyltransferase protein protected these mice from methylnitrosourea-induced tumorigenesis.
1 This work was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan.
2 To whom requests for reprints should be addressed, at Department of Biology, Fukuoka Dental College, Fukuoka 814-01, Japan.
Received 1/10/97. Accepted 4/21/97.
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