Methylnitrosourea-induced tumorigenesis in MGMT gene knockout mice

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.