Published and unpublished data for this review were identified by searches of MEDLINE, EMBASE, and references from relevant articles. Search terms used include: ‘colon cancer’, ‘colorectal cancer’, ‘rectal cancer’, ‘apoptosis’, ‘chemoprevention’, and ‘nonsteroidal antiinflammatory drug’. We also contacted researchers at institutions such as the Johns Hopkins Hospital, the Dana-Farber Cancer Institute, and the Harvard Medical School. We consulted drug companies including Wyeth-Ayerst
ReviewNonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention
Section snippets
Chemoprevention and NSAID-mediated apoptosis
How do NSAIDs exert their chemopreventive effects? A growing body of work suggests that modulation of the pathway for programmed cell death (apoptosis) in colon cells is one of the main ways in which these drugs exert their effects. Apoptosis is an important mechanism of colonocyte loss during crypt maturation31 and, during colonic carcinogenesis, it is progressively inhibited.32 Apoptosis is suppressed in sporadic adenomas, carcinomas of the colon, and in the flat, rectal mucosa of patients
COX 2-dependent mechanisms
One of the primary pharmacological properties of the NSAID family of drugs is their ability to inhibit the cyclooxygenase enzymes.42, 43 Both COX 1 and COX 2 are involved in the pathway by which arachidonic acid molecules are converted into eicosanoids. The difference between the two COX isoforms lies in their distribution in the body and physiological function. COX 2 is the isoform most likely to be important in the pathogenesis of colorectal cancer. Analysis of COX expression shows that COX 2
Conclusions
The mechanisms by which NSAIDs exert their chemopreventive effects is currently an area of heated debate. Examination of the observations made about the mechanism of NSAID chemoprevention leads, at first, to two contradictory conclusions: that NSAIDs act by a COX-dependent and a COX-independent mechanism. However, these mechanisms are not mutually exclusive, and it is likely that NSAIDs act both ways, at least in part.figure 5 summarises the chemopreventive mechanisms of action of NSAIDs, but
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