Carcinogenesis, Vol. 20, No. 12, 2355-2360,
December 1999
© 1999 Oxford University Press
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Inhibition of O6-methylguanine-DNA methyltransferase increases azoxymethane-induced colonic tumors in rats
Department of Medicine and
1 Department of Pathology, University of Chicago, Chicago, IL 60637 and
2 Carcinogen-Modified Nucleic Acid Chemistry, ABL-Basic Research Program, NCI–FCRDC, Frederick, MD, USA
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 ß-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 ß-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.
Abbreviations: 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.
3 To whom correspondence should be addressed at: Department of Medicine, MC 4076, University of Chicago Hospitals and Clinics, 5841 South Maryland Avenue, Chicago, IL 60637, USA Email: mbissonn{at}medicine.bsd.uchicago.edu
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