Yonsei Med J.  2007 Dec;48(6):1020-1027. 10.3349/ymj.2007.48.6.1020.

Sulindac Prevents Esophageal Adenocarcinomas Induced by Gastroduodenal Reflux in Rats

• Kim SW
• Jang TJ
• Jung KH
• Suh JI

• KMID: 1786219
• DOI: http://doi.org/10.3349/ymj.2007.48.6.1020

Abstract

PURPOSE: It is known that cyclooxygenase (COX)-2 expression is increased in Barrett's esophagus and esophageal adenocarcinomas. We studied COX-2 expression and the effect sulindac has on the genesis of Barrett's esophagus and adenocarcinoma in rats undergoing esophagogastroduodenal anastomosis (EGDA). MATERIALS AND METHODS: Fifty-one rats were divided into a control group (n=27), a 500ppm sulindac-treated group (n=15) and 1000 ppm sulindac-treated group (n=9). Randomly selected rats were killed by diethyl ether inhalation at 20 and 40 weeks after surgery. RESULTS: At 40 weeks, rats treated with 1000 ppm sulindac showed narrower esophageal diameter and milder inflammation than the control rats. At 40 weeks, the incidence of Barrett's esophagus was similar between control and sulindac-treated groups, but the incidence of adenocarcinoma was significantly lower in the 1000ppm sulindac-treated group than either the control or 500 ppm sulindac-treated groups. COX-2 was significantly increased in the lower esophagus of control rats killed at 40 weeks. Cyclin D1 expression was negligible in the sulindac- treated group compared with the control group. CONCLUSION: We suggest that the chemopreventive effect of sulindac is related to decreased COX-2 and cyclin D1 expression, which may be influenced by reduced inflammation.

Keyword

Barrett's esophagus; esophageal adenocarcinoma; COX-2; sulindac

MeSH Terms

Adenocarcinoma/etiology/metabolism/*prevention & control
Animals
Antineoplastic Agents/therapeutic use
Barrett Esophagus/etiology/metabolism/prevention & control
Blotting, Western
Cyclin D1/metabolism
Cyclooxygenase 2/metabolism
Duodenogastric Reflux/*complications
Esophageal Neoplasms/etiology/metabolism/*prevention & control
Immunohistochemistry
Male
Proliferating Cell Nuclear Antigen/metabolism
Rats
Rats, Sprague-Dawley
Sulindac/*therapeutic use

Figure

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  Fig. 1 The lower esophageal diameter of rats undergoing esophagogastroduodenal anastomosis for 20 weeks (A) and 40 weeks (B) according to sulindac treatment. Values are expressed as means ± SD. At 40 weeks, rats treated with 1000 ppm sulindac showed a diameter narrower than that of the control rats (p < 0.05).

• 

  Fig. 2 Lower esophageal inflammation in rats undergoing esophagogastroduodenal anastomosis for 20 weeks (A) and 40 weeks (B) according to sulindac treatment. At 40 weeks, rats treated with 1000 ppm sulindac showed milder inflammation than control rats or those treated with 500 ppm sulindac (p < 0.05).

• 

  Fig. 3 Histological findings (A, B) and immunohistochemical staining for BrdU (C, D) in the lower esophagus. Rats undergoing EGDA showed intestinal metaplasia including goblet cells above the esophagoduodenal junction (A) and adenocarcinoma characterized by abundant mucin secretion (B). BrdU-labeled columnar cells were located in the upper and lower portions of Barrett's esophagus (C). In duodenal mucosa, proliferating cells were mainly restricted to the isthmic portion (D). Magnification, × 200.

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  Fig. 4 Incidence of Barrett's esophagus and adenocarcinoma in rats undergoing esophagogastroduodenal anastomosis for 20 weeks (A) and 40 weeks (B) according to sulindac treatment. At 40 weeks, the adenocarcinoma incidence was significantly lower in rats treated with 1000 ppm sulindac than in the controls or 500 ppm sulindac-treated rats (p = 0.05).

• 

  Fig. 5 Western blot analysis of COX-2 and cyclin D1 expression in the lower esophagus of sham surgery rats and rats undergoing esophagogastroduodenal anastomosis for 20 weeks and 40 weeks according to sulindac treatment. Forty µg of protein was separated by 12% SDS-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. Immunoblots were probed with COX-2 and cyclin D1 antibodies. The bottom represents β-actin, which was used as a loading control.

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  Fig. 6 Western blot analysis of COX-2 and PCNA expression in the lower esophagus, stomach, and duodenum of rats undergoing esophagogastroduodenal anastomosis for 40 weeks. Forty µg of protein was separated by 12% SDS-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. Immunoblots were probed with COX-2 and PCNA antibodies. The bottom represents β-actin, which was used as a loading control.

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