COX-2 Inhibitors New Prevention Strategy for Colon Cancer

BUFFALO, NY—Colorectal cancer is caused by a multistep process, taking up to 25 years for an adenocarcinoma to develop. This offers multiple opportunities for prevention strategies to intervene and decrease the incidence of this disease.

“Colorectal cancer is a problem in the developed world—particularly the United States, New Zealand, Australia, Argentina, and Europe,” Raymond DuBois, MD, PhD, Minna C. Wallace Professor of Medicine and Cell Biology, Vanderbilt University Medical Center, said at the New Horizons in Cancer Prevention Symposium, hosted by Roswell Park Cancer Institute. “It appears that environment and behavior play critical roles in the development of this disease.”

The potential for a preventive agent to decrease the incidence of colorectal cancer has already been shown in regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). “There are multiple epidemiologic studies indicating that people who take aspirin on a regular basis, for at least 10 years, have a profound decrease, of almost 50%, in their colorectal cancer risk,” Dr. DuBois said.

The proposed mechanism of how aspirin and NSAIDs create antitumor activity is not completely understood, but one possible mechanism is their ability to inhibit prostaglandin production. These agents inhibit cyclooxygenase (COX) activity, which decreases the production of proinflammatory prostaglandins.

Two COX isoforms have been identified, and most NSAIDs inhibit both.

COX-1 is expressed in many cells, including normal colon tissue. COX-2 appears to be associated with colorectal adenocarcinomas, in that more than 80% of colon cancers express COX-2, compared with normal tissue in the same patient.

“This increase in COX-2 in cancerous tissue offers a target in the cancer cells. We have found that COX-2 upregulation in colon cancer cells makes the cells resistant to apoptosis. This may explain why COX-2 increases the neoplastic potential of certain cells,” Dr. DuBois said.

In a recent study, patients with familial adenomatous polyposis (FAP) who received celecoxib (Celebrex), a COX inhibitor approved for arthritis, had a 28% decrease in polyp number, a 5% decrease in polyp size, and a 31% decrease in overall polyp burden, compared with FAP participants who received a placebo for 6 months (Table).

“We need to investigate whether remaining polyps in these patients changed during celecoxib therapy,” Dr. DuBois said, “and to look at how celecoxib affects polyp recurrence and the long-term effects of this therapy. It is also possible that this prevention strategy can be applied to other epithelial tumors.”