Is COX‐2 inhibition a panacea for cancer prevention?

The epidemiologic evidence and rodent studies suggest strongly that nonselective inhibitors of cyclooxygenase (COX) enzymes such as aspirin, inhibiting both COX‐1 and COX‐2 isoforms, reduce the incidence of and mortality from intestinal tumors. Genetically manipulated animals show that both Cox‐1 and Cox‐2 disruptions decrease the tumor yield, both in genetically predisposed and in carcinogen‐treated mice. The mechanisms by which COX‐1 and COX‐2 deficiency decrease tumorigenesis are still unknown. Cox‐2 overexpression increased the tumor yield in mammary glands of the multiparous, but not virginal female transgenic mice using the murine mammary tumor virus promoter. The Cox‐2 protein was strongly induced during pregnancy and lactation. These data suggest that Cox‐2 overexpression may be an important target for cancer chemoprevention. This finding was supported by the observed cancer‐preventive effects of the COX‐2‐specific inhibitors in humans and in rodents. However, based on the available data, we cannot totally attribute the cancer preventive effects of nonsteroidal antiinflammatory drugs (NSAIDs) to COX‐2 alone—even COX‐1 may have an important role in cancer prevention as suggested by the Cox‐1 ‐deficient Min mice. It is likely that COX‐1 plays a more important role in NSAID‐induced toxicity in humans, such as in gastric ulcer formation—but inhibition of COX‐2 may not be without toxic manifestations either, as suggested by the poor survival of the Cox‐2 ‐nulled mice. Combinations of COX‐2 inhibitors with other agents that target other pathways in carcinogenesis may be a more efficacious and a less toxic strategy in cancer chemoprevention. © 2001 Wiley‐Liss, Inc.