| [ Summary ] |
Accumulated evidence has indicated that non steroidal anti-inflammatory drugs (NSAIDs) suppress intestinal polyps in familial adenomatous polyposis (FAP) and reduce the incidence of colorectal cancer. The target enzyme of NSAIDs is cyclooxygenase (COX), which catalyzes prosta glandin biosynthesis. Two isozymes, COX-1 and COX-2 have been identified while COX-1 is a constitutive enzyme, COX-2 expression is induced by stimulation with various agents, such as cytokines, mitogens, serum and endotoxins. Induction of COX-2 expression is observed in stromal cells of intestinal polyp tissues, while it is not detected in the normal intestine. Inhibition of the COX-2 enzyme by gene disruption in Apc delta716 knockout mice, a model for FAP, results in significant suppression of intestinal polyposis. Furthermore, feeding Apc delta716 mice with chow containing a COX-2 selective inhibitor reduced the nomber of polyps significantly, in a dose-dependent manner. These results provide direct evidence that COX-2 inhibitors are a novel class of therapeutic drugs for polyposis, and suitable chemopreventive agents for colorectal cancer. Interestingly, COX-1 gene disruption in polyposis mouse modes also caused decreases in the intestinal polyp number, indicating that prostaglandins produced by the COX-1 pathway are required for tumor cell growth before COX-2 is induced in polyp tissues. |