Cyclooxygenase Inhibitors and Cancer: The Missing Pieces

At 125, aspirin still represents the cornerstone of anti-platelet therapy for the acute treatment and long-term prevention of atherothrombosis. The development of a selective regimen of low-dose aspirin for the inhibition of platelet thromboxane pro-duction was key to maximizing its antithrombotic efficacy and minimizing its gastrointestinal toxicity. Based on about 50 ob-servational studies, published over the past 30 years, aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The apparent chemopreventive effect of aspirin has been confirmed in post-hoc analyses of randomized cardio-vascular trials and their meta-analyses. Moreover, prevention of sporadic colorectal adenoma recurrence was demonstrated by randomized controlled trials of low-dose aspirin and selective cy-clooxygenase-2 inhibitors. A single placebo-controlled random-ized trial of aspirin has shown long-term colorectal cancer prevention in patients with the Lynch syndrome. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the existing evi-dence for a chemopreventive effect of aspirin and other cyclooxy-genase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle.SIGNIFICANCE STATEMENT Low-dose aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The sequential involve-ment of thromboxane-dependent platelet activation and cyclo-oxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the evidence for a che-mopreventive effect of aspirin and other cyclooxygenase inhibi-tors and discuss the missing pieces of this mechanistic and clinical puzzle.

Automated summary

Low-dose aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer and possibly other digestive tract cancers. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. This mini-review aims to analyze the evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle.