Chemopreventive efficacy of sulindac sulfone against colon cancer depends on time of administration during carcinogenic process

Epidemiological and model studies with laboratory animals have provided evi dence that nonsteroidal anti-inflammatory drugs reduce the risk of colon ca ncer. Sulindac, a nonsteroidal anti-inflammatory drug, has been shown to in hibit azoxymethane (AOM)-induced colon carcinogenesis in rats when administ ered continuously before, during, and after carcinogen treatment (initiatio n and postinitiation periods) or when given continuously beginning 14 weeks after carcinogen administration (promotion/progression stage). The present study was designed to investigate the chemopreventive efficacy of sulindac sulfone (exisulind), the sulfone metabolite of sulindac, when administered during the promotion/progression stage of colon carcinogenesis in comparis on to the effect during the initiation and postinitiation periods. We have also studied the modulating effect of exisulind on colonic tumor apoptosis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0%, 0.06%, and 0.12% exisulind. At 7 weeks of age, groups of animals were injec ted s.c. with AOM (15 mg/kg body weight, once weekly for 2 weeks). Animals intended for the promotion/progression study and receiving 0% exisulind wer e switched to an experimental diet containing 0.12% exisulind at 14 weeks a fter the second AOM treatment. All rats remained on their respective dietar y regimens until the termination of the study, 50 weeks after the second AO M injection. Colon tumors were evaluated histopathologically for tumor type . Administration of 0.06% and 0.12% exisulind during the initiation and pos tinitiation periods significantly inhibited the incidence and multiplicity of invasive and/or noninvasive adenocarcinomas of the colon. The inhibition of colon tumorigenesis by exisulind was associated with a significant reta rdation of body weight gain shortly after sulfone administration and increa sed apoptosis in the colon tumors. In contrast, administration of the highe r dose (0.12%) of exisulind during the promotion/progression stage had only minimal effects on colon tumorigenesis and apoptosis in the colon tumors, suggesting that early administration, but not late administration, may be r equired for chemopreventive efficacy of this drug.