Celecoxib Colorectal Bioavailability and Chemopreventive Response in Familial Adenomatous Polyposis Patients

Abstract

ABSTRACTThe chemopreventive activity of celecoxib against colorectal cancer is limited to a proportion of familial adenomatous polyposis (FAP) patients who experience a response. The cause of this response variability and the potential mechanisms underlying these responses remain poorly understood. Preclinical studies showed that celecoxib increases the production of main oxidative metabolism product of linoleic acid, 13-S-hydroxyoctadecadienoic acid (13-S-HODE), to suppress colorectal tumorigenesis. We conducted a phase II clinical study to determine whether celecoxib increases 13-S-HODE production in colonic adenomas from FAP patients. Twenty seven FAP patients completed a 6-month oral course of 400 mg of celecoxib twice a day and had colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and obtain colorectal normal and polyp biopsies to measure celecoxib, 13-HODE, 15-HETE, 12-HETE, and LTB4 levels by LC/MS. Celecoxib levels in sera from those patients were also measured before treatment and 2, 4, and 6 months of treatment. Seventeen of the 27 patients experienced a response to celecoxib, with a more than 30% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in FAP patients.