Celecoxib Colorectal Bioavailability and Chemopreventive Response in Patients with Familial Adenomatous Polyposis

Abstract

Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven patients with FAP completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-S-hydroxyoctadecadienoic acid (13-HODE), 15-HETE, 12-HETE, and LTB4 levels by LC/MS-MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% 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 patients with FAP.

Prevention relevance: This study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in patients with FAP. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in patients with FAP. See related Spotlight, p. 205.

Conflict of interest statement

AUTHORS’ DISCLOSURES

The authors declare no competing interests.

©2021 American Association for Cancer Research.

Figures

Figure 1.. Celecoxib levels in colorectal tissues and sera in humans and mice.

A-I. FAP patients (n = 27) received 400 mg of oral celecoxib twice per day for 6 months. Colonoscopy was performed to assess polyp burden and collect colorectal tissue samples before and 6 months after celecoxib treatment. (A) Celecoxib response statuses for each patient, based on the response cut-off of polyp tumor burden reduction by ≥ 28% from the baseline (brown dotted line). (B-D) Comparisons of celecoxib levels in sera at 2 (B), 4 (C), and 6 (D) months of celecoxib treatment in patients who did and did not experience a celecoxib response. Lines represent medians. (E-G) Comparisons of celecoxib levels in paired sera and normal colorectal tissues (E), paired sera and polyps (F), or (G) paired normal colorectal tissues and polyps at six months of celecoxib treatment. Lines represent means. Correlation analyses of celecoxib levels between sera and normal colorectal tissues at six months of celecoxib treatment in the 19 of 27 FAP patients who experienced a response (H) and in the 8 of 27 FAP patients who did not experience a response (I). (J) Comparison of celecoxib levels in normal and polyp colorectal tissue samples from ApcΔ580 mice. 14-week-old ApcΔ580 mice received celecoxib (200 mg/kg/day) via gavage for 5 consecutive days (n = 6 mice) and then were euthanized. Celecoxib levels of the paired colorectal tumor and their adjacent normal colorectal tissues are shown.

Figure 2.. Effects of celecoxib on generations of colorectal lipoxygenase products in FAP patients.

The indicated lipoxygenase products were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) in normal tissues and polyps before and 6 months after celecoxib treatment. (A, D, G) Comparisons of 13-HODE (A), 15-HETE (D), and 12-HETE (G) levels in paired normal and polyp colorectal tissue samples from FAP patients prior to celecoxib treatment (n = 27). Lines represent means. (B, C, E, F, H and I) Comparisons of 13-HODE (B and C), 15-HETE (E and F), and 12-HETE (H and I) levels between pre- and post- 6 months of celecoxib treatment in normal and polyp colorectal tissues of FAP patients who did (n = 18) and did not (n = 7) experience a celecoxib response. Lines represent medians.