SUPPRESSION OF INTESTINAL POLYPOSIS IN APC(DELTA-716) KNOCKOUT MICE BY INHIBITION OF CYCLOOXYGENASE 2 (COX-2)

Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H-2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effec ts of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc( Delta 716) knockout mice, a model of human familial adenomatous polypo sis. A Ptgs2 null mutation reduced the number and size of the intestin al polyps dramatically. Furthermore, treating Apc(Delta 716) mice with a novel COX-2 inhibitor reduced the polyp number more significantly t han with sulindac, which inhibits both isoenzymes. These results provi de direct genetic evidence that COX-2 plays a key role in tumorigenesi s and indicate that COX-2-selective inhibitors can be a novel class of therapeutic agents for colorectal polyposis and cancer.