Arthritis enzyme linked to diseases

February 2, 1999

An enzyme implicated as one cause of pain and inflammation in arthritic joints may also play a role in a wide range of medical conditions, from Alzheimer's disease to colon cancer, researchers say.

The enzyme, cyclooxygenase-2, or COX-2, is the target of drugs that are being developed as alternatives to aspirin and other nonsteroidal anti-inflammatory medications, or NSAIDS, now on the market.

These NSAIDs inhibit the activity of both forms of cyclooxygenase — COX-1, which helps maintain platelet and kidney function, and COX-2, which produces substances that cause joint inflammation.

Because they affect blood platelets, NSAIDs can lead to stomach ulcers and gastrointestinal bleeding, says Peter E. Lipsky of the University of Texas Southwestern Medical Center, Dallas. New drugs in development inhibit only COX-2, says Lipsky, who chaired a workshop on COX-2 last week in Hawaii.

"It's less than 10 years since the target of these drugs (COX-2) was discovered and because it was so obvious this would be an important target, drug development began," he says.

"At the same time," Lipsky adds, "more basic science has been done looking at the role of this cyclooxygenase in other disease."

Scientists have been working on "parallel learning curves," he says, researching both "the role of this enzyme in conditions we didn't anticipate, and at same time (developing) drugs to inhibit it."

Scientists presented papers on the role of COX-2 in:

Alzheimer's disease. Researchers at Mt. Sinai Medical Center in New York reported finding twice as much COX-2 in brains of Alzheimer's victims as in healthy brains. They think the elevated enzyme level may contribute to the formation of protein plaque that kills brain cells.

Colon cancer. Scientists at Vanderbilt University Medical Center say the enzyme may help regulate growth of new blood vessels in cancer cells.

COX-2 levels were up to 50 times higher in tumor cells, compared with cells in normal tissue from the same patients. Studies at the University of Wisconsin Medical School found COX-2 inhibitors suppressed colon cancer tumors in mice.

Kidney disease. Vanderbilt researchers believe COX-2 may influence blood flow in kidneys, possibly playing a role in chronic kidney injury. In rat studies, when COX-2 was blocked, less kidney damage occurred.

Bone preservation. A link between increased COX-2 activity and the development of osteoporosis was reported by researchers at the University of Connecticut School of Medicine, based on studies in mice. More research is needed to learn the mechanism by which this may occur, and to see if COX-2 inhibitors help reverse or prevent the process, researchers said.

COX-2 inhibitors from Searle and Merck probably will be presented to the Food and Drug Administration for evaluation soon, Lipsky says. "The drugs appear as though they'll be quite useful in a variety of painful conditions and a number of inflammatory conditions."

Initially, they'll be aimed at treating pain, rheumatoid arthritis and osteoarthritis.

By Anita Manning, USA TODAY