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The cyclooxygenase (COX) enzymes (COX-1 and COX-2) are key enzymes of prostaglandin (PG) biosynthesis. Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of both COX-1 and COX-2. Selective COX-2 inhibitors have been developed that appear to have 50% less gastrointestinal toxicity than traditional nonselective NSAIDs. Experimental evidence suggests that the COX pathway is involved in tumor promotion. Evidence to support this comes from both clinical and laboratory findings suggesting that chronic NSAID use reduces the relative risk for developing colorectal cancer (CRC). Although the precise mechanism or mechanisms by which these drugs affect tumor progression is not completely understood, it is likely that part of their anti-tumor effect is due to inhibition of the COX-2 enzyme. COX-2 levels are increased in CRC as well as in several other solid malignancies. COX-2–derived bioactive lipid products promote tumor-associated neovascularization, inhibit cell death, and stimulate cell proliferation and motility. Additionally, treatment with COX-2–selective inhibitors reduces polyp burden in animal models of intestinal neoplasia and in humans with familial adenomatous polyposis (FAP). Ongoing human clinical trails are underway to test the efficacy of COX-2–selective inhibitors in a number of human cancers.