Methylnitrosourea-induced Tumorigenesis in MGMT Gene Knockout Mice

Abstract

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.