Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients

Frank A Sinicrope, Elizabeth Half, Jeffrey S. Morris, Patrick M. Lynch, Jason D. Morrow, Bernard Levin, Ernest T. Hawk, Deborah S. Cohen, Gregory D. Ayers, L. Clifton Stephens, R. K S Phillips, M. H. Wallace, B. P. Saunders, G. Steinbach, W. Hittelman, S. Patterson, R. N. DuBois, G. B. Gordon

Research output: Contribution to journalArticle

57 Citations (Scopus)

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 (PGE 2) 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 46 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.

Original languageEnglish (US)
Pages (from-to)920-927
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume13
Issue number6
StatePublished - Jun 2004

Fingerprint

Celecoxib
Adenomatous Polyposis Coli
Polyps
Adenoma
Placebos
Cell Proliferation
Dinoprostone
Mucous Membrane
Biomarkers
Apoptosis
Chemoprevention

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients. / Sinicrope, Frank A; Half, Elizabeth; Morris, Jeffrey S.; Lynch, Patrick M.; Morrow, Jason D.; Levin, Bernard; Hawk, Ernest T.; Cohen, Deborah S.; Ayers, Gregory D.; Stephens, L. Clifton; Phillips, R. K S; Wallace, M. H.; Saunders, B. P.; Steinbach, G.; Hittelman, W.; Patterson, S.; DuBois, R. N.; Gordon, G. B.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 13, No. 6, 06.2004, p. 920-927.

Research output: Contribution to journalArticle

Sinicrope, FA, Half, E, Morris, JS, Lynch, PM, Morrow, JD, Levin, B, Hawk, ET, Cohen, DS, Ayers, GD, Stephens, LC, Phillips, RKS, Wallace, MH, Saunders, BP, Steinbach, G, Hittelman, W, Patterson, S, DuBois, RN & Gordon, GB 2004, 'Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients', Cancer Epidemiology Biomarkers and Prevention, vol. 13, no. 6, pp. 920-927.
Sinicrope, Frank A ; Half, Elizabeth ; Morris, Jeffrey S. ; Lynch, Patrick M. ; Morrow, Jason D. ; Levin, Bernard ; Hawk, Ernest T. ; Cohen, Deborah S. ; Ayers, Gregory D. ; Stephens, L. Clifton ; Phillips, R. K S ; Wallace, M. H. ; Saunders, B. P. ; Steinbach, G. ; Hittelman, W. ; Patterson, S. ; DuBois, R. N. ; Gordon, G. B. / Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients. In: Cancer Epidemiology Biomarkers and Prevention. 2004 ; Vol. 13, No. 6. pp. 920-927.
@article{b5d7607d269e4eae8e3cb57217c0e7fb,
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 E2 (PGE 2) 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 46 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.",
author = "Sinicrope, {Frank A} and Elizabeth Half and Morris, {Jeffrey S.} and Lynch, {Patrick M.} and Morrow, {Jason D.} and Bernard Levin and Hawk, {Ernest T.} and Cohen, {Deborah S.} and Ayers, {Gregory D.} and Stephens, {L. Clifton} and Phillips, {R. K S} and Wallace, {M. H.} and Saunders, {B. P.} and G. Steinbach and W. Hittelman and S. Patterson and DuBois, {R. N.} and Gordon, {G. B.}",
year = "2004",
month = "6",
language = "English (US)",
volume = "13",
pages = "920--927",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients

AU - Sinicrope, Frank A

AU - Half, Elizabeth

AU - Morris, Jeffrey S.

AU - Lynch, Patrick M.

AU - Morrow, Jason D.

AU - Levin, Bernard

AU - Hawk, Ernest T.

AU - Cohen, Deborah S.

AU - Ayers, Gregory D.

AU - Stephens, L. Clifton

AU - Phillips, R. K S

AU - Wallace, M. H.

AU - Saunders, B. P.

AU - Steinbach, G.

AU - Hittelman, W.

AU - Patterson, S.

AU - DuBois, R. N.

AU - Gordon, G. B.

PY - 2004/6

Y1 - 2004/6

N2 - 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 (PGE 2) 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 46 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.

AB - 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 (PGE 2) 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 46 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.

UR - http://www.scopus.com/inward/record.url?scp=2942627339&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2942627339&partnerID=8YFLogxK

M3 - Article

C2 - 15184247

AN - SCOPUS:2942627339

VL - 13

SP - 920

EP - 927

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 6

ER -