Thioproline inhibits development of esophageal adenocarcinoma induced by gastroduodenal reflux in rats.
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.
Kumagai
Hitomi
H
Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Ohtsu, Shiga 520-2192, Japan.
Mukaisho
Ken-ichi
K
Sugihara
Hiroyuki
H
Miwa
Koichi
K
Yamamoto
Gaku
G
Hattori
Takanori
T
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
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