Non-steroidal anti-inflammatory drugs with activity against either cyclooxygenase 1 or cyclooxygenase 2 inhibit colorectal cancer in a DMH rodent model by inducing apoptosis and inhibiting cell proliferation

Background-Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce t he risk of colorectal cancer by 40-60% but the mechanism by which this occu rs is uncertain. Selective cyclooxygenase2inhibitors arepotentiallyidealche mopreventive agents as they are less toxic than standard NSAIDs. No study h as compared the efficacy of these drugs at clinically relevant doses in a t umour model. Aims-To assess the efficacy of a range of NSAIDs with varying activity agai nst the two cyclooxygenase isoforms in a rodent colorectal carcinogen model at antiinflammatory doses and to explore the effect of NSAIDs on the rate of tumour apoptosis and proliferation. Methods-Colorectal tumours were induced in six week old Sprague-Dawley rats with five weekly doses of 1,2 dimethylhydrazine. Test agents were: indomet hacin 2 mg/kg/day, meloxicam 0.6 mg/kg/ day, celecoxib 6 mg/kg/day, and sul indac sulphone 40 mg/kg/day. Sulindac was tested at its chemoprotective dos e of 20 mg/kg/day. After 23 weeks the number and volume of tumours per anim al were recorded. Histology was performed. Tumour apoptosis was quantified on haematoxylin-eosin sections. Tumour proliferation was quantified using a n immunohistochemical stain for bromodexoyuridine incorporation. Results-Test agents effectively reduced the number and volume of tumours de veloping in the treatment period. In all groups there was an increase in th e rate of tumour apoptosis and a reduced rate of proliferation. Conclusions-These data suggest that the chemopreventive effect of NSAIDs is independent of their cyclooxygenase inhibitory profile. One potential mech anism for their action may be through induction of apoptosis and inhibition of proliferation.