TY - JOUR
AU - Ramesh K. Wali, Susan Skarosi, John Hart, Yingchun Zhang, M.eileen Dolan, Robert C. Moschel, Lan Nguyen, Reba Mustafi, Thomas A. Brasitus, Marc Bissonnette
AB - Azoxymethane (AOM) causes O 6 -methylguanine adduct formation which leads to G→A transitions. Their repair is carried out by O 6 -methylguanine-DNA methyltransferase (MGMT). To evaluate the importance of this repair event in AOM-induced carcinogenesis, we examined the effect of O 6 -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 O 6 -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. Key words AOM, azoxymethane ASOH, allele-specific oligonucleotide hybridization BG, O 6 -benzylguanine MGMT, O 6 -methylguanine-DNA methyltransferase PEG, polyethylene glycol PM-RFLP, primer-mediated restriction fragment length polymorphism SSCP, single strand conformational polymorphism. © Oxford University Press « Previous | Next Article » Table of Contents This Article Carcinogenesis (1999) 20 (12): 2355-2360. doi: 10.1093/carcin/20.12.2355 » Abstract Free Full Text (HTML) Free Full Text (PDF) Free Classifications Short Communication Services Article metrics Alert me when cited Alert me if corrected Find similar articles Similar articles in Web of Science Similar articles in PubMed Add to my archive Download citation Request Permissions Citing Articles Load citing article information Citing articles via CrossRef Citing articles via Scopus Citing articles via Web of Science Citing articles via Google Scholar Google Scholar Articles by Wali, R. K. Articles by Bissonnette, M. 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TI - Inhibition of O6-methylguanine-DNA methyltransferase increases azoxymethane-induced colonic tumors in rats
JF - Carcinogenesis
DO - 10.1093/carcin/20.12.2355
DA - 1999-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/inhibition-of-o6-methylguanine-dna-methyltransferase-increases-2Y54dP0igs
SP - 2355
VL - 20
IS - 12
DP - DeepDyve
ER -