Gastroenterology

Gastroenterology

Volume 123, Issue 1, July 2002, Pages 60-67
Gastroenterology

Clinical–Alimentary Tract
Rofecoxib inhibits cyclooxygenase 2 expression and activity and reduces cell proliferation in Barrett's esophagus,☆☆

https://doi.org/10.1053/gast.2002.34244Get rights and content

Abstract

Background & Aims: Cyclooxygenase 2 (COX-2) is overexpressed in Barrett's esophagus and adenocarcinoma and up-regulated by acid or bile salt exposure. COX-2 inhibition with the selective inhibitor rofecoxib may be important in chemoprevention of esophageal adenocarcinoma by decreasing cell proliferation. Methods: Biopsy specimens of esophagus, Barrett's esophagus, and duodenum were obtained at baseline from 12 patients and were compared with biopsy specimens obtained after 10 days of therapy with rofecoxib 25 mg orally daily. All patients were maintained asymptomatic on their proton pump inhibitor therapy throughout the study. COX-2 expression, proliferating cell nuclear antigen (PCNA) expression (proliferation marker), and prostaglandin E2 (PGE2) biopsy content (marker of COX activity) were assessed by immunoblotting and enzyme immunoabsorbence assays. Results: At baseline, COX-2 expression was 3-fold higher in Barrett's esophagus than esophagus and duodenum (P < 0.05). After rofecoxib therapy, COX-2 expression in Barrett's esophagus decreased by 77% (P < 0.005). Similarly at baseline, PGE2 content was 2-fold higher in Barrett's esophagus than esophagus or duodenum. After rofecoxib therapy, PGE2 content decreased in Barrett's esophagus by 59% (P < 0.005). At baseline, PCNA expression was also 2-fold higher in Barrett's esophagus than squamous esophagus and duodenum (P < 0.005). After rofecoxib therapy, PCNA expression in Barrett's esophagus decreased by 62.5% (P < 0.005). Conclusions: Rofecoxib 25 mg orally once daily reduces COX-2 expression, PGE2 release, and cell proliferation in Barrett's esophagus. Together with acid suppressive therapy, rofecoxib may be a promising chemoprevention agent against dysplasia and esophageal adenocarcinoma.

GASTROENTEROLOGY 2002;123:60-67

Section snippets

Patients and tissue collection

Over an 8-month period, 12 eligible patients with BE undergoing endoscopic surveillance at the Veterans Affairs Palo Alto Health Care System and Stanford University Hospital were selected for participation because they fulfilled the study inclusion and exclusion criteria and expressed interest in the study. Inclusion criteria were age >18 years, endoscopic and histologic evidence of BE on earlier endoscopy, and willingness to undergo repeat endoscopy and biopsies 10 days after rofecoxib

Clinical characteristics

The clinical characteristics of the patients studied are given in Table 1.

. Patient demographic and clinical data

Gender (M/F)11/1
Age (mean ± SD) (yr)67.5 ± 7.8 (47–79)
Length of Barrett's esophagus (mean ± SD) (cm)2.4 ± 1.6 (0.5–6)
Hiatal hernia length (mean ± SD) (cm)1.5 ± 1.7 (0–4)
PPI therapy
With omeprazole (mean ± SD) (mg/day)32.5 ± 10 (n = 8)
With lansoprazole (mean ± SD) (mg/day)38.6 ± 14 (n = 4)
Duration of PPI therapy (mean ± SD) (yr)5.5 ± 3.1 (0.5–10)
H. pylori statusNegative (n = 12)
Lower

Discussion

The results of our study suggest that, in contrast to normal esophagus or duodenum, the metaplastic BE epithelium is associated with enhanced proliferation, COX-2 expression, and PGE2 content that can be attenuated in vivo by rofecoxib therapy at the standard dose of 25 mg orally once daily. Therefore, our study is the first to suggest that, in conjunction with acid-suppressive therapy, selective COX inhibition may be useful as a chemopreventive strategy against Barrett's adenocarcinoma by

Acknowledgements

The authors thank the faculty, fellows, and staff of the Endoscopy Units of the Veterans Affairs Palo Alto Health Care System and Stanford University Hospital for their assistance in retrieval of mucosal specimens.

References (47)

  • SJ Shiff et al.

    Nonsteroidal anti-inflammatory drugs and colorectal cancer: Evolving concepts of their chemopreventive actions

    Gastroenterology

    (1997)
  • M Tsujii et al.

    Alterations in cellular adhesion and apoptosis in epithelial cells over-expressing prostaglandin endoperoxide synthase-2

    Cell

    (1995)
  • VN Shirvani et al.

    Cyclooxygenase-2 expression in Barrett's esophagus and esophageal adenocarcinoma: ex vivo induction by bile salts and acid exposure

    Gastroenterology

    (2000)
  • BJ Reid et al.

    Endoscopic biopsies diagnose high-grade dysplasia or early operable adenocarcinoma without grossly recognizable neoplastic lesions

    Gastroenterology

    (1988)
  • TJ Schnitzer et al.

    The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis

    Clin Ther

    (1999)
  • H Sheng et al.

    Induction by cyclooxygenase-2 by activated H-ras oncogene in rat-1 fibroblasts and the role of mitogen activated protein kinase pathway

    J Biol Chem

    (1998)
  • CD Morris et al.

    Cyclooxygenase-2 expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence

    Am J Gastroenterol

    (2001)
  • N Buttar et al.

    Chemopreventive potential of selective cyclooxygenase-2 (COX-2) inhibition in Barrett's epithelium: an in vitro study (abstr)

    Gastroenterology

    (2000)
  • NS Buttar et al.

    Can cyclooxygenase-2 inhibitors prevent cancer in an animal model of Barrett's esophagus? A randomized, placebo-controlled chemoprevention trial (abstr)

    Gastroenterology

    (2001)
  • T Bammer et al.

    Rationale for surgical therapy in Barrett's esophagus

    Mayo Clin Proc

    (2001)
  • NJ Shaheen et al.

    Is there publication bias in the reporting of cancer risk in Barrett's esophagus?

    Gastroenterology

    (2000)
  • BJ Reid et al.

    Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify high- and low-risk patients subsets

    Am J Gastroenterol

    (2000)
  • SR DeMeester et al.

    The diagnosis and management of Barrett's esophagus

    Adv Surg

    (1999)
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    Address requests for reprints to: George Triadafilopoulos, M.D., Chief, Gastroenterology Section (111-GI), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304. e-mail: [email protected]; fax: (650) 856-8024.

    ☆☆

    Supported in part by the American College of Gastroenterology (to O.L.) and by Merck (to G.T.).

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