Cancer and the Cyclo-Oxygenase Enzyme
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The cyclo-oxygenase (COX) metabolic pathway and prostaglandin (PG) production appear to play a causal role in the promotion and progression of human cancers. COX-1 and COX-2 are the enzymes that convert arachidonic acid into PGs and thromboxanes. COX-2 has received a great deal of attention recently because it is commonly overexpressed in a wide range of cancers and precancerous lesions (e.g. in colon, lung, prostate and breast), and elevated production of prostanoids (particularly prostaglandin [PGE2]) via COX-2 is associated with several pro-carcinogenic effects including: increased proliferation, apoptosis resistance, host immunosuppression, tumor neoangiogenesis, and increased metastatic potential. Inhibitors of COX-1 and COX-2 (e.g. aspirin and most other nonsteroidal anti-inflammatory drugs) and of COX-2 alone (e.g. celecoxib and rofecoxib) have shown cancer preventative efficacy in epidemiological studies, experimental studies in laboratory animals, and in human clinical trials. Because of their improved tolerability profile, COX-2 selective inhibitors appear to hold substantial promise for long-term administration in the setting of cancer prevention. Emerging data suggest that these agents may have potential in cancer treatment as well. This article attempts to comprehensively review the role of the COX pathway in tumorigenesis, and the mechanisms, safety, and efficacy of COX nonselective and COX-2 selective inhibitors for cancer chemopreventive and chemotherapeutic applications.