Journal Article

Inhibition of <i>O</i><sup>6</sup>-methylguanine-DNA methyltransferase increases azoxymethane-induced colonic tumors in rats

Ramesh K. Wali, Susan Skarosi, John Hart, Yingchun Zhang, M.eileen Dolan, Robert C. Moschel, Lan Nguyen, Reba Mustafi, Thomas A. Brasitus and Marc Bissonnette

in Carcinogenesis

Volume 20, issue 12, pages 2355-2360
Published in print December 1999 | ISSN: 0143-3334
Published online December 1999 | e-ISSN: 1460-2180 | DOI:
Inhibition of O6-methylguanine-DNA methyltransferase increases azoxymethane-induced colonic tumors in rats

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Azoxymethane (AOM) causes O6-methylguanine adduct formation which leads to G→A transitions. Their repair is carried out by O6-methylguanine-DNA methyltransferase (MGMT). To evaluate the importance of this repair event in AOM-induced carcinogenesis, we examined the effect of O6-benzylguanine (BG), a potent inhibitor of MGMT, on colonic tumor development. Rats were treated weekly for 2 weeks at 0 and 24 h with BG (60 mg/kg body wt i.p.) or vehicle (40% polyethylene glycol, PEG-400), followed 2 h after the first dose of BG with AOM (15 mg/kg body wt) or vehicle (saline) i.p. Rats were killed 35 weeks later and tumors harvested and DNA extracted. In the AOM-treated groups, BG caused a significant increase in tumor incidence with tumors in 65.9%, versus 30.8% in the AOM/PEG-treated group (P < 0.05). In the BG/AOM group there was also a significant increase in tumor multiplicity, with 2.3 tumors/tumor-bearing rat, versus 1.6 tumors/tumor- bearing rat in the AOM/PEG group (P < 0.05). Since O6-methylguanine adducts can cause activating mutations in the K-ras and β-catenin genes, we examined the effects of BG on these mutations. In the BG group there were seven mutations in codon 12 or 13 of exon 1 of the K-ras gene in 51 tumors examined, compared with no K-ras mutations in 17 tumors analyzed in the AOM/PEG group (P = 0.12). In the BG/AOM group there were 10 mutations in exon 3 of the β-catenin gene among 48 tumors evaluated, compared with six mutations in 16 tumors analyzed in the PEG/AOM group (P = 0.16). In summary, MGMT inhibition increases AOM-induced colonic tumor incidence and multiplicity in rats.

Keywords: AOM, azoxymethane; ASOH, allele-specific oligonucleotide hybridization; BG, O6-benzylguanine; MGMT, O6-methylguanine-DNA methyltransferase; PEG, polyethylene glycol; PM-RFLP, primer-mediated restriction fragment length polymorphism; SSCP, single strand conformational polymorphism.

Journal Article.  4604 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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