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.

Abstract

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/micrograms 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.

• Authors: N H Zaidi, T P Pretlow, M A O'Riordan, L L Dumenco, E Allay, S L Gerson
• Journal: Carcinogenesis (Carcinogenesis) Vol. 16 Issue 3 Pg. 451-6 (Mar 1995) ISSN: 0143-3334 [Print] England
• PMID: 7697797 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Codon
• DNA Primers
• Guanine
• Methyltransferases
• O(6)-Methylguanine-DNA Methyltransferase
• Adenine
• Azoxymethane

Topics

• Adenine
• Animals
• Azoxymethane (toxicity)
• Base Sequence
• Codon
• Colon (drug effects, pathology)
• DNA Primers
• DNA Repair
• Genes, ras
• Guanine
• Humans
• Intestinal Mucosa (drug effects, pathology)
• Methyltransferases (genetics)
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Mutation
• O(6)-Methylguanine-DNA Methyltransferase