Cell Proliferation and Apoptotic Indices Predict Adenoma Regression in a Placebo-Controlled Trial of Celecoxib in Familial Adenomatous Polyposis Patients

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Abstract
Background: Celecoxib was shown to regress colorectal adenomas in familial adenomatous polyposis (FAP) patients relative to placebo. To address the mechanism of polyp regression, we determined whether celecoxib can modulate cell proliferation, apoptosis, and prostaglandin E2 (PGE2) levels in colorectal epithelia from FAP trial participants and whether such alterations correlate with observed reductions in polyp number. Materials and Methods: Colorectal mucosal biopsies were obtained at baseline and on last day of celecoxib (100 or 400 mg twice daily) or placebo administration (6 months). Residual paraffin-embedded adenomas and normal mucosa from the same patients (n = 17) or normal tissue alone (n = 15) were analyzed. Immunoperoxidase staining for Ki-67 was performed and apoptotic cells were identified by their morphology. Ki-67 and apoptotic labeling indices and their ratios were calculated in superficials (s) and nonsuperficial (ns) regions of adenomas and normal mucosa, and baseline to 6-month differences were calculated. PGE2 levels were analyzed by mass spectroscopy (normal, n = 64; adenoma, n = 56). Biomarkers were analyzed by treatment arm and correlated with previously determined mean percentage reductions in colorectal polyp number. Results: In adenomas, a reduction in the superficial proliferative activity i.e., Ki-67s labeling index, accompanied polyp regression (r = −0.76, P = 0.006). An increase in the apoptotic ratio [i.e., superficial apoptotic index (AIs)/nonsuperficial apoptotic index (AIns)] was found to correlate with reduced polyp counts in that higher apoptotic ratios correlated with better response to celecoxib (r = 0.71, P = 0.004). Furthermore, the AIs/Ki-67s ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a trend toward increased AIs (r = 0.33, P = 0.053) and polyp regression was found. PGE2 levels did not significantly correlate with polyp regression. Changes in biomarker levels (baseline to 6 months) were correlated in adenomas and normal mucosa (AIs, r = 0.29, P = 0.024; AIns, r = 0.34, P = 0.009; PGE2, r = 0.50, P = 0.059) within individual patients. Conclusion: Suppression of cell proliferation and an increased apoptotic ratio, as well as the ratio of apoptosis to cell proliferation, accompany polyp regression in a chemoprevention trial in FAP patients. These findings suggest potential mechanisms for the efficacy of celecoxib and warrant further study of these biomarkers as intermediate endpoints in FAP patients.