New Chemoprevention Trials of COX-2 Inhibitors Underway

NEW YORK—The markedly improved safety profile of selective COX-2 inhibitors over conventional nonsteroidal anti-inflammatory drugs (NSAIDs) has spurred a number of new studies aimed at demonstrating their value as preventive agents among populations at high and moderate risk for a variety of cancers, Andrew J. Dannenberg, MD, said at a media briefing. Dr. Dannenberg is professor of medicine and surgery, Weill Medical College of Cornell University.

Investigators at Cornell and Strang Cancer Prevention Center have initiated a study of more than 2,000 patients worldwide to evaluate whether COX-2 inhibitors will prevent sporadic colorectal adenomas. “Sporadic colorectal adenomas represent a very important target for preventing colon cancer,” Dr. Dannenberg said. “We’re interested in identifying medications that prevent recurrence of adenomas.”

Another trial will evaluate the effectiveness of COX-2 inhibitors in Barrett’s esophagus, a premalignancy that predisposes to esophageal adenocarcinoma. Further studies of the preventive role of COX-2 inhibitors are planned for bladder cancer and oral leukoplakia.

The therapeutic action of NSAIDs is thought to be due to inhibition of COX-2, whereas their gastrointestinal toxicity is believed to be due to inhibition of COX-1. NSAIDs, which inhibit both COX-1 and COX-2, are responsible for an estimated 100,000 hospitalizations and as many as 16,500 deaths a year in the United States alone, Dr. Dannenberg said.

“With the development of selective COX-2 inhibitors, we can expect dramatic improvement in these numbers and hence can begin to consider using these agents for prevention of cancer,” he said.

In the less than 2 years since celecoxib (Celebrex), the first selective COX-2 inhibitor, was granted FDA approval, this new class of drugs has revolutionized the treatment of osteoarthritis. Rofecoxib (Vioxx) was the second selective COX-2 inhibitor to receive FDA approval.

In 1999, the FDA granted approval for the use of celecoxib for the treatment of familial adenomatous polyposis (FAP). In preapproval trials, celecoxib reduced overall tumor burden by an average of 31%, over a 6-month course of treatment, with some FAP patients achieving as much as an 80% reduction and some as little as 10%.

Theoretical Basis of Trials

Dr. Dannenberg, who is also director of cancer prevention at Weill, is involved in an initiative with the American Association for Cancer Research and the FDA to develop guidelines to expedite drug development for premalignant lesions. At the press briefing, he outlined the theoretical basis of the new COX-2 inhibitor cancer prevention trials.

Cyclooxygenase (COX) is an enzyme that catalyzes the synthesis of prostaglandins from arachidonic acid, he said. Prostaglandins have been implicated in carcinogenesis. In the early 1990s, it was discovered that there are two isoforms of COX, each occupying a place on a different chromosome.

COX-1, a constitutive gene, fulfills a homeostatic function in the GI tract. COX-2, an inducible gene, is an immediate early response gene that is induced by growth factors, proinflammatory cyto-kines, carcinogens, oncogenes, and tumor promoters.

COX-2 can convert tobacco procar-cinogens into carcinogens. Further, high levels of COX-2 promote angiogenesis, feeding tumor blood supply, and inhibit apoptosis, leading to unregulated cell growth.

COX-2 is overexpressed in at least 85% of colorectal cancers and in half of all premalignant adenomas, Dr. Dannenberg said. It is also overexpressed in malignancies of the breast, lung, liver, pancreas, skin, bladder, cervix, stomach, esophagus, and head and neck.