Scientists at the American Health Foundations Nutritional Carcinogenesis Division, under the direction of Dr. Bandaru S. Reddy, division chief and associate director of the Foundations Naylor Dana Institute, Valhalla, New York, and Dr. Karen Seibert of Searle Research & Development, St. Louis, Missouri, described an exceptionally strong inhibitor of colon cancer development in an animal model assay in the February 1, 1998, issue of Cancer Research.
Dietary administration of the cyclooxygenase-2 inhibitor celecoxib (SC-5 8635; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-IH-pyrazol-l-l]benzenesulfonamide)
suppressed colon tumor incidence by 93% and multiplicity of colon tumors by 97% in a model assay in F344 rats that uses azoxymethane as the colon carcinogen.
Inhibition of Cyclooxygenase Enzyme
This study provides exciting evidence in support of the hypothesis that prostaglandin modulation, which is catalyzed by the cyclooxygenase enzymes (COX-1 and COX-2) in the arachidonic acid cascade, is involved in colon tumorigenesis and that blocking COX-2 activity leads to inhibition of tumor development. While COX- l is regarded as an enzyme that is expressed to generate prostaglandins during normal physiologic functions, the isozyme COX-2 can be induced by various agents, including growth factors and tumor promoters, and increased COX-2 expression has been measured in colon tumors.
The study showed that the specific inhibition of COX-2 by celecoxib affords chemopreventive strength beyond that seen in previous studies with nonsteroidal anti-inflammatory agents, such as aspirin. It further demonstrated that celecoxib has no toxic side effects (in the gastrointestinal tract or kidneys) like those seen with some of the nonsteroidal anti-inflammatory agents on the basis of inhibition of the constitutive enzyme COX-l.
Celecoxib is currently in phase III clinical trials for the treatment of arthritis. Further preclinical testing of celecoxib as an anticancer agent is scheduled, and researchers hope that these tests will lead to clinical trials in humans for confirmation of the chemopreventive potential of this promising agent against colon cancer in humans.