Is inhibition of cyclooxygenase required for the chemopreventive effect ofNSAIDs in colon cancer? A model reconciling the current contradiction

NSAIDs are powerful chemopreventive agents for colon cancer, but their mech anism of action remains unknown. Their best recognized pharmacological prop erty is inhibition of the enzyme cyclooxygenase (COX), which catalyzes the synthesis of prostaglandins; however, additional effects are well documente d. Current studies on the mechanism of the chemopreventive effect of NSAIDs lead to two contradictory conclusions: NSAIDs prevent colon cancer either by inhibiting the activity of COX, or through mechanisms that do not requir e COX inhibition. To resolve this apparent conflict, after examining severa l alternatives, we propose a model, which assumes that both mechanisms are correct but that they exert their effect either on different steps of the m ultistep process of colon carcinogenesis or on different control mechanisms . This postulated dual action of NSAIDs may explain their remarkable effect iveness in colon cancer prevention. Unraveling these mechanistic details ca n be very rewarding for the design of more refined approaches to cancer che moprevention and for a deeper understanding of colorectal carcinogenesis. ( C) 2000 Harcourt Publishers Ltd.