Original Article
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World J Gastroenterol. Sep 21, 2012; 18(35): 4866-4874
Published online Sep 21, 2012. doi: 10.3748/wjg.v18.i35.4866
Indomethacin but not a selective cyclooxygenase-2 inhibitor inhibits esophageal adenocarcinogenesis in rats
Paula Esquivias, Antonio Morandeira, Alfredo Escartín, Carmelo Cebrián, Sonia Santander, Francisco Esteva, María Asunción García-González, Javier Ortego, Angel Lanas, Elena Piazuelo
Paula Esquivias, María Asunción García-González, Javier Ortego, Angel Lanas, Elena Piazuelo, CIBER Digestive and Hepatic Deseases, 08036 Barcelona, Spain
Antonio Morandeira, Alfredo Escartín, Service of Surgery, University Hospital “Lozano Blesa”, 50009 Zaragoza, Spain
Carmelo Cebrián, Javier Ortego, Service of Pathology, University Hospital “Lozano Blesa”, 50009 Zaragoza, Spain
Sonia Santander, Angel Lanas, Department of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
Francisco Esteva, Service of Clinical Biochemistry, University Hospital “Lozano Blesa”, 50009 Zaragoza, Spain
María Asunción García-González, Angel Lanas, Elena Piazuelo, Aragon Health Science Institute, 50009 Zaragoza, Spain
Angel Lanas, Service of Gastroenterology, University Hospital “Lozano Blesa”, 50009 Zaragoza, Spain
Author contributions: Esquivias P wrote the manuscript; Morandeira A and Escartín A carried out all surgical procedures; Cebrián C and Ortego J performed histological analysis; Santander S, García-González MA and Esteva F were involved in all biochemical determinations and provided vital reagents and analytical tools; Lanas A and Piazuelo E were involved in the design of the study, statistical analysis and editing the manuscript.
Supported by Instituto de Salud Carlos III (CIBERehd); MF-tricyclic was supplied free of charge by Merck Frosst Canada Inc.
Correspondence to: Paula Esquivias, BSc, CIBER Digestive and Hepatic Deseases, Cardenal Goma s/n, 08036 Barcelona, Spain. pauesquivias@gmail.com
Telephone: +34-652-960252 Fax: +34-976-765478
Received: November 29, 2011
Revised: May 17, 2012
Accepted: June 15, 2012
Published online: September 21, 2012
Abstract

AIM: To evaluate the effects of indomethacin [dual cyclooxygenase (COX)-1/COX-2 inhibitor] and 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2-(5H)-furanone (MF-tricyclic) (COX-2 selective inhibitor) in a rat experimental model of Barrett’s esophagus and esophageal adenocarcinoma.

METHODS: A total of 112 surviving post-surgery rats were randomly divided into three groups: the control group (n = 48), which did not receive any treatment; the indomethacin group (n = 32), which were given 2 mg/kg per day of the COX-1/COX-2 inhibitor; and the MF-tricyclic group (n = 32), which received 10 mg/kg per day of the selective COX-2 inhibitor. Randomly selected rats were killed either 8 wk or 16 wk after surgery. The timing of the deaths was in accordance with a previous study performed in our group. Only rats that were killed at the times designated by the protocol were included in the study. We then assessed the histology and prostaglandin E2 (PGE2) expression levels in the rat esophagi. An additional group of eight animals that did not undergo esophagojejunostomy were included in order to obtain normal esophageal tissue as a control.

RESULTS: Compared to a control group with no treatment (vehicle-treated rats), indomethacin treatment was associated with decreases in ulcerated esophageal mucosa (16% vs 35% and 14% vs 17%, 2 mo and 4 mo after surgery, respectively; P = 0.021), length of intestinal metaplasia in continuity with anastomosis (2 ± 1.17 mm vs 2.29 ± 0.75 mm and 1.25 ± 0.42 mm vs 3.5 ± 1.54 mm, 2 mo and 4 mo after surgery, respectively; P = 0.007), presence of intestinal metaplasia beyond anastomosis (20% vs 71.4% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P = 0.009), severity of dysplasia (0% vs 71.4% and 20% vs 85.7% high-grade dysplasia, 2 mo and 4 mo after surgery, respectively; P = 0.002), and adenocarcinoma incidence (0% vs 57.1% and 0% vs 60%, 2 mo and 4 mo after surgery, respectively; P < 0.0001). Treatment with the selective COX-2 inhibitor, MF-tricyclic, did not prevent development of intestinal metaplasia or adenocarcinoma. In parallel, we observed a significant decrease in PGE2 levels in indomethacin-treated rats, but not in those treated with MF-tricyclic, at both 2 mo and 4 mo. Compared to control rats that did not undergo surgery (68 ± 8 ng/g, P = 0.0022 Kruskal-Wallis test) there was a significant increase in PGE2 levels in the esophageal tissue of the rats that underwent surgery either 2 mo (1332 ± 656 ng/g) or 4 mo (1121 ± 1015 ng/g) after esophagojejunostomy. However, no differences were found when esophageal PGE2 levels were compared 2 mo vs 4 mo post-esophagojejunostomy. At both the 2- and 4-mo timepoints, we observed a significant decrease in PGE2 levels in indomethacin-treated rat esophagi compared to those in either the control or MF-tricyclic groups (P = 0.049 and P = 0.017, respectively). No differences in PGE2 levels were found when we compared levels in rats treated with MF-tricyclic to not-treated rats.

CONCLUSION: In this rat model of gastrointestinal reflux, indomethacin was associated with a decrease in the severity of esophagitis and reduced development of esophageal intestinal metaplasia and adenocarcinoma.

Keywords: Intestinal metaplasia; Esophageal adenocarcinoma; Indomethacin; MF-tricyclic