Transgenic expression of human MGMT protects against azoxymethane-induced aberrant crypt foci and G to A mutations in the K-ras oncogene of mouse colon

• Published in: Carcinogenesis (New York) 1995-03, Vol.16 (3), p.451-456
• Main Authors: Zaidi, Nasir H., Pretlow, Theresa P., O'Riordan, Mary Ann, Dumenco, Luba L., Allay, Esther, Gerson, Stanton L.
• Format: Article
• Language: English
• Subjects: Adenine; Animals; Azoxymethane - toxicity; Base Sequence; Codon; Colon - drug effects; Colon - pathology; DNA Primers; DNA Repair; Genes, ras; Guanine; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Methyltransferases - genetics; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; O-Methylguanine-DNA Methyltransferase
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/16.3.451

Transgenic mice over-expressing MGMT, which codes for the human protein O6-alkylguanine-DNA alkyltransferase, are protected from methylating agent-induced thymic lymphomas. In this study we evaluated the ability of transgenic overexpression of MGMT in the colon to protect mice from the development of azoxymethane(AOM)-induced aberrant crypt foci (ACF) and mutations in K-ras. Colonic alkyltransferase in MGMT+ transgenic mice was > 5-fold higher than in nontransgenics: 10.5 ± 1.1 vs 2.2 ± 1.1 fmol/μg DNA, P = > 0.0001. Mice received 20 mg AOM/kg i.p. at 6 weeks or 15 mg AOM/kg at 6 and 7 weeks of age, and 8 wks later colons were examined for ACF. A significant protective effect of MGMT was seen in mice given single dose of 20 mg AOM/kg. The incidence of ACF/colon was lower in MGMT+ mice (2.0 ± 1.2) than in nontransgenic mice (3.9 ± 1.8, P = 0.02). G to A mutations in codon 12 of K-ras were detected by PCR-RFLP in ACF and in random samples of normal appearing mucosa. The incidence of ACF with mutant K-ras in MGMT transgenic mice (0.6 ± 0.7/colon) was significantly reduced compared to nontransgenic mice (2.3 ± 1.7/colon, P = 0.02). We propose that AOM induces at least two overlapping but not identical premalignant lesions (aberrant crypt foci and K-ras mutations) which can be prevented by over-expression of MGMT. Thus, MGMT may protect colonic mucosa from carcinogenesis involving methylating agents such as AOM.