Cancer prevention: a new era beyond cyclooxygenase-2.

The seminal epidemiological observation that nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon and possibly other cancers has spurred novel approaches to cancer prevention. The known inhibitory effect of NSAIDs on the eicosanoid pathway prompted studies focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. Their efficacy in the prevention of sporadic colon and other cancers remains unknown; one COX-2 inhibitor has been withdrawn because of side effects, and there are concerns about whether these effects are class-specific. There is evidence to suggest that COX-2 may not be the only or ideal eicosanoid pathway target for cancer prevention. Six sets of observations support this notion: the relatively late induction of COX-2 during carcinogenesis; the finding that NSAIDs may not require inhibition of COX-2 for their effect; the modest effect of coxibs in cancer prevention; that currently available coxibs have multiple non-COX-2 effects that may account for at least some of their efficacy; the possibility that concurrent inhibition of COX-2 in non-neoplastic cells may be harmful; and the possibility that COX-2 inhibition may modulate alternative eicosanoid pathways in a way that promotes carcinogenesis. Given the limitations of COX-2-specific inhibitors and the biological evidence mentioned above, we suggest that targets other than COX-2 should be pursued as alternative or complementary approaches to cancer prevention.