COX2 Inhibitors Promising in Prevention

PHILADELPHIA—Several phase II clinical trials are now underway to test chemoprevention of colon cancer through selected cyclooxygenase enzyme (COX2) inhibitors.

“The degree of inhibition of colon tumors by these agents has been found to be much greater than that seen with the commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), Bandura S. Reddy, MD, said in his delivery of the Dewitt Goodman Lecture at the annual meeting of the American Association for Cancer Research.

Dr. Reddy, associate director, American Health Foundation, and research professor, Department of Microbiology, New York Medical College, Valhalla, was recognized for his major contributions to the understanding of the role of nutritional and other protective factors in relation to colon carcinogenesis.

Twenty-Five Years of Research

His research for 25 years constitutes the experimental basis for the most promising current approaches to colon cancer prevention in humans, the AACR said in honoring Dr. Reddy. Through his development of animal models for studies of the effects of dietary components on experimentally induced colon cancers, his research has provided clear demonstration of the preventive roles of dietary fiber, omega-3 fatty acids, and many plant phenolics and terpenoids.

Most recently his studies have focused on the class of COX2 inhibitors, which promise to provide the protective activity of agents such as aspirin without the gastric side effects associated with COX1 inhibition. “In fact, subduing COX1 can cause side effects, including ulcers, intestinal bleeding, and, less often, kidney damage,” Dr. Reddy said.

Although the mechanisms by which NSAIDs inhibit colon carcinogenesis are not clearly elucidated, he said, one possibility is the inhibition of COX1 and COX2, leading to a reduction of eicosanoid production that affects cell proliferation and tumor growth and enhances apoptosis.

COX1 appears to be constitutively expressed and is thought to carry out primarily housekeeping functions at relatively constant levels of expression, Dr. Reddy said.

COX2, on the other hand, is produced mainly in pathologic conditions such as cancer. Expression of COX2 is rapidly induced by growth factors, oncogenes, and tumor promoters, he noted, and overex-pression of COX2 has been observed in colon tumors.

Most of the commonly used NSAIDs have very little selectivity for COX1 or COX2. More specific, yet minimally toxic, inhibitors of COX2 that reduce prostaglandin synthesis without affecting prostaglandin levels in normal tissues (resulting from COX1 activity) could serve as effective chemopreventive agents.

Several studies have indicated that administration of selective COX2 inhibitors to laboratory animals suppressed chemically induced colonic aberrant crypt foci, early preneoplastic lesions, and colon tumors, suggesting that these agents inhibit very early and advanced lesions in the colon, Dr. Reddy said.

Based on these preclinical studies, several human phase II chemoprevention trials of selected COX2 inhibitors are in progress in patients with colon polyps.