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.
Sakumi
K
K
Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Shiraishi
A
A
Shimizu
S
S
Tsuzuki
T
T
Ishikawa
T
T
Sekiguchi
M
M
D000818:Animals; D002273:Carcinogens; D018628:Gene Dosage; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008223:Lymphoma / Q000473:pathology; D008770:Methylnitrosourea; D008780:Methyltransferases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019853:O(6)-Methylguanine-DNA Methyltransferase; D015996:Survival Rate; D013953:Thymus Neoplasms / Q000139:chemically induced* / Q000473:pathology
D002273:Carcinogens; D008770:Methylnitrosourea; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase