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

Carcinogenesis. 1995 Mar;16(3):451-6. doi: 10.1093/carcin/16.3.451.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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(6)-Methylguanine-DNA Methyltransferase

Substances

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