Cyclooxygenase-2 inhibitors in tumorigenesis (Part I)

The rate-limiting enzyme in arachidonate metabolism is mediated by enzymes known as cyclooxygenases (COXs), These enzymes catalyze the biosynthesis of prostaglandin H-2, 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 enzyme, 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 inhibit both COX-1 and COX-2, these drugs also cause unwanted side effects, exemplified by gastrointestinal bleeding. Accumulating evidence indicates that nonsteroidal anti-inflammatory drugs can reduce the incidence of colorectal cancers in human and experimental animals and can reduce the polyp number and size in patients with familial adenomatous polyposis. This Part I (of a two-part review) focuses on the discovery of the COXs; their biochemical, molecular, and structural properties; and on the discovery of isozyme-specific inhibitors of COX activity.