Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation

Nonsteroidal anti-inflammatory drug (NSAID) use reduces the risk of colorec tal cancer by 40-50%. Previous studies suggest that effective inhibition of colorectal cancer by NSAIDs may be dependent on the presence or absence of a K-ras mutation. This study was aimed at determining the relationship bet ween inhibition of colorectal cancer by sulindac and sulindac sulfone and t he presence of activating K-ras mutations in the 1,2-dimethylhydrazine dihy drochloride rat model. Sulindac (20 mg.kg(-1).day(-1)), sulindac sulfone (4 0 mg.kg(-1).day(-1)), or vehicle was administered orally to male Sprague-Da wley rats for a 4-wk period beginning 20 wk after tumor induction. Tumor nu mber and volume were measured before treatment by laparotomy and colonoscop y and again after treatment. Sulindac and sulindac sulfone treatment signif icantly reduced the number and volume of colorectal tumors compared with co ntrol rats. For K-ras (codon 12) mutation detection, frozen tumor tissue wa s collected at the endpoint. We found K-ras codon 12 mutations in 11 of 21 (52%) control tumors. The proportion of tumors with K-ras mutations in the sulindac-treated group [5 of 8 (62%); odds ratio = 1.51 (95% confidence int erval = 0.29, 8.33)] and the proportion of sulindac sulfone-treated tumors [9 of 14 (64%); odds ratio = 1.63 (95% confidence interval = 0.41, 6.66)] w ere not significantly different from controls. Tumor inhibition did not cor relate with K-ras (codon 12) mutation status, which suggests that the mecha nism of inhibition of rat colorectal cancer by sulindac and sulindac sulfon e is independent of K-ras mutation.