PHILADELPHIASeveral 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
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.