Non-steroidal anti-inflammatory drugs with different cyclooxygenase inhibitory profiles that prevent aberrant crypt foci formation but vary in acute gastrotoxicity in a rat model

Background: Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer; however, their use as preventive agents is l imited by their inherent toxicity. Drugs that selectively inhibit cyclooxyg enase-2 (COX-2) may be useful in this setting as they are supposedly less t oxic. No study has directly compared the ability of standard NSAIDs and sel ective COX-2 inhibitors to inhibit colorectal cancer at clinically relevant doses. Methods: Aberrant crypt foci (ACF) were induced in Sprague-Dawley rats by u sing 1,2-dimethylhydrazine (DMH). Test agents or vehicle were then administ ered for 3 weeks, twice daily through orogastric gavage. At the end of this period, the number and multiplicity of ACF were determined. The agents tes ted at equivalent anti-inflammatory doses were: sulindac and indomethacin ( standard NSAIDs), meloxicam (selective COX-2 inhibitor), celecoxib (specifi c COX-2 inhibitor) and sulindac sulfone (no known COX activity). Acute gast rotoxicity of NSAID in rats was compared by using quantitative histology. Results: All test agents reduced the number of ACE There was a 42% reductio n with indomethacin, 46% with sulindac, 46% with meloxicam, 22% with celeco xib and 36% with sulindac sulfone. Only the COX-2 inhibitors caused no sign ificant gastrotoxicity in rats. Conclusions: Cyclooxygenase-2 inhibitors are potentially ideal chemoprevent ive agents as they inhibit ACF and are not gastrotoxic. (C) 2000 Blackwell Science Asia Pty Ltd.