Cancer prevention: A new era beyond cyclooxygenase-2

The seminal epidemiological observation that nonsteroidal antiinflammatory drugs ( NSAIDs) prevent colon and possibly other cancers has spurred novel approaches to cancer prevention. The known inhibitory effect of NSAIDs on the elcosanoid pathway prompted studies focusing on cyclooxygenase ( COX) and its products. The increased prostaglandin E 2 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 Their efficacy in the prevention of sporadic colon and other cancers remains unknown; one COX- 2 inhibitor has been withdrawn because of side effects, and there are concerns about whether these effects are class-specific.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.