title: Thioproline inhibits development of esophageal adenocarcinoma induced by gastroduodenal reflux in rats.
abstract: Several epidemiological cohort studies have suggested that duodeno-gastroesophageal reflux per se induces Barrett's esophagus leading to increased risk of the development of esophageal adenocarcinoma (EAC). However, the exact causative factors behind EAC remain unclear. Recently, we designed a new duodenal contents reflux model which retained normal stomach function. In this model, duodenal contents flowed back into the esophagus and stomach resulting in repeated re-entry into the esophagus through the site of esophagojejunostomy. To elucidate the factors underlying the development of EAC, thiazolidine-4-carboxylic acid (thioproline, TPRO) was applied to the new reflux models as a nitrite scavenger and as a probe to detect reactive nitrogen species (RNS). Post-operatively, 31 animals were divided into two groups according to diet. Animals belonging to the control group were given normal diet (n = 18), while the TPRO group was given food containing 0.5% TPRO (n = 13). All esophageal sections in both groups were examined using hematoxylin and eosin staining and immunohistochemical analysis of inducible nitric oxide synthase (iNOS). EACs developed in 7 of 18 rats (38.9%) of the control group, whereas no EACs were detected in the TPRO group (Fisher's exact test, P < 0.05). Conversely, esophageal squamous cell carcinoma (ESCC) was detected in 1 of 18 rats (5.6%) of the control group and in 1 of 13 rats (7.7%) of the TPRO group. The incidence of ESCC was not significantly different between the two groups (P = 0.671). iNOS protein was overexpressed in Barrett's esophagus of both groups. The present results suggest that RNS such as nitric oxide and peroxynitrite and nitroso compounds derived from reflux of duodenal contents play an important role in the development of EAC, and that the primary causes of ESCC and EAC may differ.
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Ohtsu, Shiga 520-2192, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kumagai
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Mukaisho
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugihara
authors.forename: Koichi
authors.initials: K
authors.lastname: Miwa
authors.forename: Gaku
authors.initials: G
authors.lastname: Yamamoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Hattori
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001471:Barrett Esophagus / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D018196:Carcinoma, Adenosquamous / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D004032:Diet; D004383:Duodenogastric Reflux / Q000150:complications*; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009603:Nitroso Compounds / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D053778:Thiazolidines
chemical_list: D000970:Antineoplastic Agents; D009603:Nitroso Compounds; D026361:Reactive Nitrogen Species; D013844:Thiazoles; D053778:Thiazolidines; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C003438:thiazolidine-4-carboxylic acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat