"There is a lot of evidence suggesting these drugs may help to prevent cancer," says Ernest Hawk, MD, MPH, chief, gastrointestinal & other cancer research group at the division of cancer prevention of the National Cancer Institute (NCI).

Researchers have long suspected that an enzyme called cyclooxygenase (COX) might increase cancer risk, because it seemed to interfere with the normal controls over cell growth.

Studies in the 1990s suggested aspirin, thought to lower production of COX, might help prevent colorectal cancer, but doctors could not recommend aspirin because regular, long-term use of the drug can bring about stomach ulcers and intestinal bleeding.

Then, notes Hawk, scientists discovered that what they had thought was a single enzyme ? COX ? actually appears in two forms: COX-1, which is necessary to maintain health, and COX-2, which is linked to inflammation, tumor formation and growth.

Scientists interested in reducing COX-2 levels as a way of treating inflammation from arthritis quickly developed drugs that only lower levels of COX-2, without affecting COX-1, says Hawk. Cancer researchers soon began experiments to see if the COX-2 inhibitors could prevent cancer.

Results of a collaborative NCI - G.D. Searle clinical trial showed that a COX-2 inhibitor, celecoxib, reduced the number of pre-cancerous polyps occurring in the colons of people with an inherited pre-disposition to colon cancer called familial adenomatous polyposis (FAP) by an average of 28%, says Hawk. The FDA approved the drug for that use in 2000.

The success of that trial spurred NCI to design several follow-up clinical studies of celecoxib, examining people with FAP as well as another inherited pre-disposition to colon cancer, Hawk says. Another trial will look at the drug?s ability to prevent colon cancer and polyps in those with no inherited risk, but who have higher than normal risk because they had polyps or colon cancer. COX-2 is also being tested in combination with another potential prevention drug, called DFMO, to see if together they can be even more effective than COX-2 alone.

Also planned are trials to test COX-2 inhibitors in those at risk for cancers of the esophagus, bladder, skin, and prostate, because high levels of COX-2 have been found in those tumors.

Scientists don?t yet know all the ways COX-2 inhibitors may help prevent cancer, says Hawk, but they do know the drugs reduce the production of free radicals (highly reactive forms of oxygen that can damage genes), interfere with the action of carcinogens (cancer-causing substances), help restore normal controls over cell growth, and stimulate the immune system. They may also help prevent tumors from developing their own blood supply.

Hawk says the role of COX-2 inhibitors may expand to include cancer treatment, as evidenced so far in animal studies and in one small human clinical trial, in which the COX-2 inhibitor indomethacin prolonged the survival of patients with metastatic cancer. More clinical trials are planned to further evaluate these effects.

"The use of COX-2 inhibitors has considerable promise for arresting the development, and perhaps for treating, colorectal and other cancers," says Michael Thun, MD, ACS vice president of epidemiology and surveillance research. "But at this stage, the use of these drugs remains experimental except in patients with FAP, because the drugs have not been in long enough use to know whether they might have unexpected toxicities," he adds.