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Is COX-2 inhibition a panacea for cancer prevention?
1Unit of Chemoprevention, International Agency for Research on Cancer, Lyon, France. vainio@iarc.fr
Abstract:
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.
Insights
Nonselective cyclooxygenase (COX) inhibitors, like aspirin, reduce intestinal tumor incidence. Both COX-1 and COX-2 play roles in cancer prevention, though their exact mechanisms and potential toxicities require further investigation for effective chemoprevention strategies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Epidemiologic and rodent studies indicate nonselective cyclooxygenase (COX) inhibitors, such as aspirin, reduce intestinal tumor incidence and mortality.
- Genetic studies in mice demonstrate that disruptions in both COX-1 and COX-2 decrease tumor yield.
- The precise mechanisms by which COX-1 and COX-2 deficiency inhibit tumorigenesis remain unclear.
Purpose of the Study:
- To investigate the role of cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2, in intestinal tumorigenesis and cancer chemoprevention.
- To evaluate the potential of COX-2 as a target for cancer chemoprevention strategies.
- To explore the contributions of both COX-1 and COX-2 to the anti-cancer effects of nonsteroidal anti-inflammatory drugs (NSAIDs).
Main Methods:
- Review of epidemiologic evidence and rodent studies involving nonselective and selective COX inhibitors.
- Analysis of genetically manipulated animal models with disrupted or overexpressed COX-1 and COX-2 genes.
- Examination of COX-2 protein induction during pregnancy and lactation in transgenic mice.
Main Results:
- Nonselective COX inhibition is associated with reduced intestinal tumor incidence and mortality.
- Disruptions in both Cox-1 and Cox-2 genes decrease tumor yield in various mouse models.
- COX-2 overexpression increased mammary tumor yield in multiparous transgenic mice, with induction during pregnancy and lactation.
- COX-2 specific inhibitors show cancer-preventive effects, but COX-1 may also contribute to cancer prevention.
- NSAID-induced toxicity, like gastric ulcers, is linked to COX-1 inhibition, while COX-2 inhibition may have its own toxicities.
Conclusions:
- Both COX-1 and COX-2 play significant roles in intestinal tumorigenesis and cancer prevention.
- COX-2 is a potential target for cancer chemoprevention, supported by studies with selective inhibitors.
- The exact roles of COX-1 and COX-2 in cancer prevention are complex and not fully elucidated.
- Combinations of COX-2 inhibitors with agents targeting other carcinogenic pathways may offer a more effective and safer chemoprevention strategy.