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.
Vainio
H
H
Unit of Chemoprevention, International Agency for Research on Cancer, Lyon, France. vainio@iarc.fr
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*
D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases