title: Indomethacin but not a selective cyclooxygenase-2 inhibitor inhibits esophageal adenocarcinogenesis in rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CIBER Digestive and Hepatic Deseases, Cardenal Goma s/n, Barcelona, Spain. pauesquivias@gmail.com
authors.forename: Paula
authors.initials: P
authors.lastname: Esquivias
authors.forename: Antonio
authors.initials: A
authors.lastname: Morandeira
authors.forename: Alfredo
authors.initials: A
authors.lastname: Escartín
authors.forename: Carmelo
authors.initials: C
authors.lastname: Cebrián
authors.forename: Sonia
authors.initials: S
authors.lastname: Santander
authors.forename: Francisco
authors.initials: F
authors.lastname: Esteva
authors.forename: María Asunción
authors.initials: MA
authors.lastname: García-González
authors.forename: Javier
authors.initials: J
authors.lastname: Ortego
authors.forename: Angel
authors.initials: A
authors.lastname: Lanas
authors.forename: Elena
authors.initials: E
authors.lastname: Piazuelo
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000494:pharmacology*; D001471:Barrett Esophagus / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004941:Esophagitis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D004947:Esophagus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D005260:Female; D005663:Furans / Q000494:pharmacology; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007213:Indomethacin / Q000097:blood / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008679:Metaplasia; D009092:Mucous Membrane / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D008565:Membrane Proteins; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D015232:Dinoprostone; D007213:Indomethacin