REVIEW Cyclooxygenase-2 Inhibitors in Tumorigenesis (Part II)

The rate-limiting step in arachidonate metabolism is medi-ated by enzymes known as cyclooxygenases (COXs). These enzymes catalyze the biosynthesis of prostaglandin H2, the precursor of molecules such as prostaglandins, prostacyclin, and thromboxanes. The COX enzyme family consists of the classical COX-1 enzyme, which is constitutively expressed in many tissues, and a second isozyme, i.e., COX-2, which is induced by various stimuli, such as mitogens and cytokines, and is involved in many inflammatory reactions. Because nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2, these drugs also cause unwanted side effects, exemplified by gastrointestinal bleeding. Accumulat-ing evidence indicates that NSAIDs can reduce the incidence of colorectal cancers in human and experimental animals and can reduce the number and size of polyps in patients with familial adenomatous polyposis. This Part II (of a two-part review) focuses on the growing clinical and experimen-tal evidence that NSAIDS and COX-2 inhibitors can influ-ence the risk of colon (and possibly of other) cancers. [J Natl Cancer Inst 1998;90:1609–20] Cyclooxygenase (COX) is the key enzyme in arachidonate metabolism and catalyzes the biosynthesis of prostaglandin H2, the precursor for prostanoids.1 In addition to COX-1, which is constitutively expressed in many tissues, another isozyme (COX-2) was identified in 1991. COX-2 is induced in many inflammatory reactions. Because nonsteroidal anti-inflammator