Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett's esophagus.

Abstract

BACKGROUND & AIMS:

Carcinogenesis in Barrett's esophagus (BE) is associated with an increased expression of cyclooxygenase (COX) 2. However, there has been no direct evidence that inhibition of COX-2 prevents cancer in BE. We studied the effect of MF-Tricyclic, a selective COX-2 inhibitor, on the development of BE and adenocarcinoma in a rat model.

METHODS:

Four weeks after esophagojejunostomy, 105 Sprague-Dawley rats were randomized to a chow containing MF-Tricyclic or Sulindac, or a placebo. Ninety-six (92%) rats completed the study and were sacrificed at 28 +/- 2 weeks. The animals were assessed for the presence of cancer, tumor volume, BE, degree of inflammation, and COX-2 expression and activity.

RESULTS:

MF-Tricyclic and Sulindac reduced the relative risk of development of esophageal cancer by 55% (95% confidence interval [CI] = 43%-66%, P < 0.008) and by 79% (95% CI = 68%-87%, P < 0.001), respectively, compared with controls. No significant differences were noted in the risk of esophageal cancer between the MF-Tricyclic and the Sulindac group (P = 0.34). The median tumor volume was not significantly different among the 3 groups (P = 0.081). Moderate to severe degree of inflammation was significantly more common (P = 0.005) in the control compared with the MF-Tricyclic and the Sulindac group; however, the prevalence of BE was not significantly different between groups (P = 0.98). Rats in the control group had higher tissue PGE2 level compared with the MF-Tricyclic and Sulindac groups (P = 0.038).

CONCLUSIONS:

Selective and nonselective COX-2 inhibitors can inhibit inflammation, COX-2 activity, and development of adenocarcinoma induced by reflux. This provides direct evidence that COX-2 inhibitors may have chemopreventive potential in BE.

• Authors: Navtej S Buttar, Kenneth K Wang, Olga Leontovich, Jay Y Westcott, Rodney J Pacifico, Marlys A Anderson, Krishnawatie K Krishnadath, Lori S Lutzke, Lawrence J Burgart
• Journal: Gastroenterology (Gastroenterology) Vol. 122 Issue 4 Pg. 1101-12 (Apr 2002) ISSN: 0016-5085 [Print] United States
• PMID: 11910360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Furans
• Isoenzymes
• Lactones
• Sulfones
• rofecoxib
• 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases

Topics

• Adenocarcinoma (etiology, pathology, prevention & control)
• Animals
• Barrett Esophagus (complications, drug therapy, pathology)
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (blood, pharmacology)
• Disease Models, Animal
• Esophageal Neoplasms (etiology, pathology, prevention & control)
• Esophagitis (complications, pathology)
• Furans (blood, pharmacology)
• Gastroesophageal Reflux (complications, pathology)
• Isoenzymes (antagonists & inhibitors, biosynthesis, metabolism)
• Lactones (blood, pharmacology)
• Male
• Prostaglandin-Endoperoxide Synthases (biosynthesis, metabolism)
• Rats
• Rats, Sprague-Dawley
• Sulfones