Details

Autor(en) / Beteiligte

• Wali, R K
• Skarosi, S
• Hart, J
• Zhang, Y
• Dolan, ME
• Moschel, R C
• Nguyen, L
• Mustafi, R
• Brasitus, T A
• Bissonnette, M

Titel

Inhibition of O super(6)-methylguanine-DNA methyltransferase increases azoxymethane-induced colonic tumors in rats

Ist Teil von

• Carcinogenesis (New York), 1999-12, Vol.20 (12), p.2355-2360

Erscheinungsjahr

1999

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Azoxymethane (AOM) causes O super(6)-methylguanine adduct formation which leads to G arrow right A transitions. Their repair is carried out by O super(6)-methylguanine-DNA methyltransferase (MGMT). To evaluate the importance of this repair event in AOM-induced carcinogenesis, we examined the effect of O super(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 super(6)-methylguanine adducts can cause activating mutations in the K-ras and beta -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 beta -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.