Carcinogenesis Advance Access published online on January 30, 2004
Carcinogenesis, doi:10.1093/carcin/bgh067
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Ohtsu, Shiga, 520-2192, Japan; Department of Dental & Oral surgery, Shiga University of Medical Science, Seta-tsukinowa-cho, Ohtsu, Shiga, 520-2192, Japan
* Corresponding author. E-mail: mukaisho{at}belle.shiga-med.ac.jp.
Received 1 September 2003
; revised 6 December 2003
; accepted 16 December 2003
Several epidemiological cohort studies have suggested that duodeno-gastroesophageal reflux per se induces Barrett's esophagus leading to increased risk for 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 esophagus to stomach resulting in reentry to esophagus through the site of esophgojejunostomy, repeatedly. 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, thirty-one 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-eosin staining and immunohistochemical analysis of inducible nitric oxide synthase (iNOS). EACs developed in 7 out 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 out of 18 rats (5.6%) of the control group and in 1 out 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 (NO), and peroxynitrite (ONOO-) and nitroso-compounds derived from reflux of duodenal contents play an important role in the development of EAC, and the primary causes 2 of ESCC and EAC may differ.
Barrett's esophagus, gastroduodenal reflux, bile acid, thioproline, iNOS
Thioproline inhibits development of esophageal adenocarcinoma induced by gastroduodenal reflux in rats
2 Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Ohtsu, Shiga, 520-2192, Japan
3 Department of Gastroenterologic Surgery, Kanazawa University, Kanazawa, 920-8641, Japan
4 Department of Dental & Oral surgery, Shiga University of Medical Science, Seta-tsukinowa-cho, Ohtsu, Shiga, 520-2192, Japan
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