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COX-2 Inhibitors

© David Olle

The COX-2 inhibitors, Celebrex, Vioxx and Celecoxib, are a new generation of drugs for the treatment of arthritis. They alleviate the symptoms of inflammation and pain, while minimizing the harmful side effect of stomach ulcers. Fortunately, researchers have found that they also appear to have beneficial effects for the prevention and treatment on many types of cancers.

What are COX-2 inhibitors?

Physicians have typically prescribed non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, to alleviate the symptoms of inflammation and pain in arthritis sufferers. However, long-term use of these drugs is often accompanied by an increased incidence of stomach ulcers and bleeding. COX refers to cyclooxygenase, an enzyme that converts arachadonic acid (a fatty substance) into prostaglandins. Prostaglandins are hormone-like substances found in very small quantities in the body that have potent physiological effects. In attempts to develop safer drugs, researchers found that there are two structural forms of cyclooxygenase, so they were dubbed COX-1 and COX-2. COX-1 serves to maintain the mucus lining of the stomach and the integrity of the blood platelets. COX-2, on the other hand, is involved in the symptoms of pain and inflammation. COX-1 primarily serves a maintenance function with stable levels, while the gene for COX-2 is inducible, or stimulated by growth factors, cytokines, carcinogens, oncogenes and other tumor promoters. The NSAIDs inhibit both COX-1 and COX-2, which accounts for the undesirable side effects. The new drugs selectively inhibit only COX-2, and have revolutionized the treatment of arthritis.

What is the relationship of COX-2 inhibitors to cancer?

Observational studies indicate that there is a decreased incidence of colon cancer among patients taking aspirin over long periods; some studies indicate up to a 40% reduction. In an attempt to determine the cause, researchers discovered that colon cancer patients have elevated levels of COX-2 enzyme. The exact reason for this overexpression of COX-2 has not been determined, since, contrary to many other cancers, the gene that codes for this enzyme has not been shown to mutate. Studies at Vanderbilt University have demonstrated that COX-2 plays a role in angiogenesis, the growth of small blood vessels that allows tumors to continue to grow. Other studies have shown COX-2 to inhibit apoptosis. Kim and Brasitus 3suggest that NSAIDs may act by another mechanism; by binding to the receptors for prostaglandins, they may prevent the transcription of genes involved in the development of colorectal cancer.

Since COX-2 is involved in so many mechanisms of tumor formation, researchers have been studying its role in other cancers. 2Barrett's esophagus refers to precancerous lesions found in the esophagus due to acid reflux from the stomach. COX-2 overexpression is found in these tissues, but not in normal esophageal epithelium. COX-2 overexpression is found in those breast cancer tumors that also overexpress the oncogene HER2/neu. COX-2 overexpression has also been found in head and neck cancer, bladder, cervical, and non-small cell lung cancer.

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