title: Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients.
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 E(2) (PGE(2)) levels in colorectal epithelia from FAP trial participants and whether such alterations correlate with observed reductions in polyp number.
  
  
  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. PGE(2) 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-67(s) labeling index, accompanied polyp regression (r = -0.76, P = 0.006). An increase in the apoptotic ratio [i.e., superficial apoptotic index (AI(s))/nonsuperficial apoptotic index (AI(ns))] 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 AI(s)/Ki-67(s) ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a trend toward increased AI(s) (r = 0.33, P = 0.053) and polyp regression was found. PGE(2) levels did not significantly correlate with polyp regression. Changes in biomarker levels (baseline to 6 months) were correlated in adenomas and normal mucosa (AI(s), r = 0.29, P = 0.024; AI(ns), r = 0.34, P = 0.009; PGE(2), r = 0.50, P = 0.059) within individual patients.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gastrointestinal Medicine and Nutrition, University of Texas M. D. Anderson Cancer Center, Houston, USA. sinicrope.frank@mayo.edu
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Half
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Morris
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lynch
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Bernard
authors.initials: B
authors.lastname: Levin
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Hawk
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Cohen
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ayers
authors.forename: L Clifton
authors.initials: LC
authors.lastname: Stephens
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000032:analysis; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000517:prevention & control; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000032:analysis; D004311:Double-Blind Method; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000503:physiopathology; D019394:Ki-67 Antigen / Q000032:analysis; D013058:Mass Spectrometry; D008875:Middle Aged; D010919:Placebos; D011720:Pyrazoles; D012074:Remission Induction / Q000379:methods; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D015415:Biomarkers; D016861:Cyclooxygenase Inhibitors; D019394:Ki-67 Antigen; D010919:Placebos; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D015232:Dinoprostone