The importance of arachidonic acid (AA) and linoleic acid (LA) metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs that inhibit COX activity, reduce the incidence and mortality of colon cancer and reduce polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAIDs reduce both the size and number of colon tumors induced by carcinogens. Prostaglandins and other lipids play a major role in the development and progression of colon and other cancers but the mechanism is not clear. We have recently discovered that the overexpression of COX-2 in a transgenic mouse model during embryonic development results in a number of physiological defects, ultimately resulting in the death of the fetus. The most dramatic effects were on skeletal development caused by the induction of apoptosis in the sclerotome of the transgenic embryos. This was a specific response not observed in other tissues. In addition, the sclerotomal accumulation of p53 protein is observed in transgenic embryos, suggesting that COX-2 may induce apoptosis via the up-regulation of p53. The aberrant COX-2 signaling during embryonic development is teratogenic and suggests a possible association of COX-2 with fetal malformations of unknown etiology.

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