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 colorectal 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 between inhibition of colorectal cancer by sulindac and sulindac sulfone and the presence of activating K-ras mutations in the 1,2-dimethylhydrazine dihydrochloride rat model. Sulindac (20 mg x kg(-1) x day(-1)), sulindac sulfone (40 mg x kg(-1) x day(-1)), or vehicle was administered orally to male Sprague-Dawley rats for a 4-wk period beginning 20 wk after tumor induction. Tumor number and volume were measured before treatment by laparotomy and colonoscopy and again after treatment. Sulindac and sulindac sulfone treatment significantly reduced the number and volume of colorectal tumors compared with control rats. For K-ras (codon 12) mutation detection, frozen tumor tissue was 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 interval = 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)] were not significantly different from controls. Tumor inhibition did not correlate with K-ras (codon 12) mutation status, which suggests that the mechanism of inhibition of rat colorectal cancer by sulindac and sulindac sulfone is independent of K-ras mutation.
de Jong
T A
TA
Department of Surgery, Monash University Medical School, Prahran, Melbourne 3181, Australia.
Skinner
S A
SA
Malcontenti-Wilson
C
C
Vogiagis
D
D
Bailey
M
M
van Driel
I R
IR
O'Brien
P E
PE
D019813:1,2-Dimethylhydrazine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002273:Carcinogens; D003062:Codon; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D008297:Male; D009154:Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013467:Sulindac / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002273:Carcinogens; D003062:Codon; D013467:Sulindac; D019813:1,2-Dimethylhydrazine; C025463:sulindac sulfone