NEWS

Early Trials Probe COX-2 Inhibitors' Cancer-Fighting Potential

Jan Ziegler

Research into COX-2 inhibitors is expanding rapidly out of the animal testing phase, with results so far suggesting that this novel class of compounds may be useful in prevention as well as treatment of colon, skin, and bladder cancer.

The National Cancer Institute is organizing, conducting, or finishing six trials in patients to investigate a variety of endpoints in these three cancers plus Barrett's esophagus, a condition considered a precursor to cancer.

The makers of the two leading COX-2 inhibitor drugs, approved so far only for arthritis and pain relief, said they also would expand their involvement in cancer-related research this year. Searle, the Chicago-based pharmaceutical company, planned to file a new drug application soon with the Food and Drug Administration for use in oncology indications for its drug celecoxib (CelebrexTM), said Searle spokeswoman Susan Shaffer.

Before Year's End

Merck & Co. spokeswoman Kyra Lindemann said only that the Whitehouse Station, N.J., company would start studies of its rofecoxib (VioxxTM) in colon cancer at the end of the year.

Bandaru Reddy, Ph.D., associate director for research and chief of the Division of Nutritional Carcinogenesis at the American Health Foundation in Valhalla, N.Y., who with colleagues produced some of the earliest animal evidence that COX-2 inhibitors might have use in the cancer arena, described the progression of testing as "very exciting."



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Dr. Bandaru Reddy

 
"I think there is a great deal of promise with the COX-2 inhibitors based on the fact that there is a lot of epidemiological evidence and data from animal studies suggesting these drugs [non-steroidal anti-inflammatory drugs] can inhibit the development of tumors," Reddy said.

COX-2 inhibitors are non-steroidal anti-inflammatory drugs, but are designed to avoid non-steroidal anti-inflammatory drugs' major drawback: namely, that long-term use leads to a substantial risk of gastrointestinal complications, including ulcers and bleeding.

Standard NSAIDs inhibit cyclooxygenases (COXs) 1 and 2, the enzymes involved in production of prostaglandins, fatty acids that are ubiquitous in the body. But while COX-2 is active on demand, COX-1 is crucial to normal cellular function, playing a particularly important role in healthy gastrointestinal and kidney function.

Experience in studies so far show that the incidence of GI complications caused by COX-2 inhibitors, which selectively inhibit their namesake enzyme, is significantly lower than for other NSAIDs.

Nevertheless, labeling on both celecoxib and rofecoxib contains warnings about potential GI effects, and will likely continue to do so until actual risk is clarified through further study and clinical use, said FDA spokeswoman Susan Cruzan.

Animal studies have indicated that many kinds of tumors contain elevated COX-2 levels. This finding, combined with epidemiologic observations that standard NSAIDs may prevent colon cancer, led to the idea of investigating the COX-2 inhibitors' cancer-fighting potential.

But so far, the most significant hints that the drugs may fill that bill have come from studies of ultraviolet-induced skin damage, bladder cancer, and colon tumors, said Ronald Lubet, Ph.D., a program director in the NCI Division of Cancer Prevention.

One of Six

One of the six studies coordinated by NCI is an investigation of whether celecoxib could shrink or reduce the number of adenomas in 83 patients with familial adenomatous polyposis, a condition characterized by multiple bowel polyps with a high probability of turning malignant.

Results are under analysis for presentation in a major medical journal and at a conference in October, said Ernest Hawk, M.D., acting chief of the gastrointestinal cancer research group in the Division of Cancer Prevention at NCI — thus, results were not disclosed.

A second trial has begun, with the goal of investigating a number of endpoints among 80 carriers of the genetic defect responsible for hereditary non-polyposis colorectal cancer, a genetically driven condition in which few polyps are created.

Participants will range from those who are asymptomatic carriers of the genetic defect to some who have already had colon surgery for tumors, Hawk said. The researchers will monitor the drug's modulation of COX expression, adenoma development, apoptosis, and other biomarkers in bowel tissues.

Other Trials

Other trials are at the protocol evaluation stage. One will examine whether celecoxib can prevent the occurence of adenomas in people with prior colon cancer unrelated to either FAP or HNPCC.

Also in design stages are studies that will examine whether the drug can prevent second primary tumors among patients who have been treated for bladder cancer; whether it can prevent and regress the number of actinic keratoses (pre-cancerous skin lesions); and whether it can regress dysplasia and reduce carcinogenesis in Barrett's esophagus.

Raymond DuBois, M.D., director of the gastrointestinal division and the cancer prevention program at Vanderbilt University School of Medicine, Nashville, said he is cautiously optimistic that the studies will show positive results as hoped. But even if they do, important questions about optimal dosing and duration of use will remain.



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Dr. Raymond DuBois

 
Evidence from other areas of cancer treatment research suggest that up to 5 years of a therapy is often enough to prevent recurrence, several researchers said. Prevention, however, is a tougher question.

"If we've prevented a cancer for 5 years, do we keep people off the drug then?" Lubet asked. "To my thinking there's been no prospective study to answer that."

Adherence, or patient compliance, too, could be a problem.

"In heart disease, it is well-established that small doses of aspirin are extremely effective for people who have had heart attacks and maybe for those who haven't.

But adherence is extremely low," said Martin Brown, Ph.D., head of the health services and economics section within NCI's Applied Research Branch.



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Dr. Martin Brown

 
Another question is whether the new inhibitor drugs will work on any tumor that expresses high levels of COX-2. Some researchers have assumed the answer will be "yes" — but Lubet said that, too, remains to be seen.


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