The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis

Epidemiological and animal studies suggest that nonsteroidal antiinflammato ry drugs (NSAIDs) may reduce colon cancer risk. NSAIDs nonselectively inhib it both the constitutive cyclooxygenase (COX) 1 associated with side effect s and the desired therapeutic target COX-2, which is induced in inflammatio n and neoplasia, We used the adenomatous polyposis coli (Apc) mutant Min mo use model to determine whether the selective COX-2 inhibitor celecoxib is e ffective for adenoma prevention and/or regression, and whether it might be safer than the nonselective NSAID previously shown to be most effective in this model, piroxicam, Min mice (n = 120) were randomized to treatment with celecoxib (0, 150, 500, or 1500 ppm celecoxib mixed in the diet) or piroxi cam, To distinguish prevention from regression effects, groups were treated either "early" (before adenomas develop) or "late" (after most adenomas ar e established). Celecoxib caused dramatic reductions in both the multiplici ty and size of tumors in a dose-dependent manner (P < 0.01). Early treatmen t with 1500 ppm of celecoxib was effective for prevention, decreasing tumor multiplicity to 29% and tumor size to only 17% of controls (P < 0.01). Lat e treatment demonstrated regression effects, reducing tumor multiplicity an d size by about half. In contrast to the significant toxicity of piroxicam, which caused ulcers complicated by perforation and bleeding, celecoxib cau sed no gastrointestinal side effects and did not inhibit platelet thromboxa ne B-2 at plasma drug levels similar to those obtained in early clinical tr ials in humans. These results provide the first evidence that selective inh ibitors of COX-2 are safe and effective for the prevention and regression o f adenomas in a mouse model of adenomatous polyposis and strongly support o ngoing clinical trials in humans with the same syndrome. The broader popula tion of patients with common sporadic adenomas that have somatic mutations of the same gene (APC) may also benefit from this treatment approach.