The long-term goal of this project is to provide a mechanistic basis for the prevention of esophageal adenocarcinoma (EAC), a disease with a rapidly increasing incidence rate and a poor prognosis. For this purpose, the investigators have modified an esophagoduodenal anastomosis (EDA) model by giving iron supplements to rats. This model mimics human esophageal pathogenesis by causing chronic gastroduodenal-esophageal reflux and producing Barrett's esophagus (BE) and EAC, without the use of any carcinogen. Their hypothesis is that oxidative cellular damage, which is caused by reflux-induced inflammation, is a major factor driving the EAC pathogenic process, and thus preventable with the use of antioxidants and anti-inflammatory agents. They will test this hypothesis in the rat model and develop prevention approaches with the following specific aims: 1) To improve the nutritional status of the animals in their model and to investigate the effect of iron nutrition on oxidative cellular damage and the formation of BE/EAC. Rats (after surgery) will be maintained on an enriched AIN93 diet and supplemented with iron by different routes. Parameters reflecting inflammation and oxidative cellular damage and the formation of BE/EAC will be studied. 2) To test the hypothesis that oxidative stress is a major causative factor for the pathogenesis of EAC by studying its inhibition by antioxidative nutrients (agents). The effects of vitamin E, selenium, and N-acetylcysteine supplementation on oxidative damage parameters and their relationship with esophageal pathogenesis will be investigated. 3) To investigate the possible inhibition of BE/EAC formation by nonsteroidal anti-inflammatory drugs (NSAIDs). Sulindac, sulindac sulfone, and selective cyclooxygenase 2 (COX-2) inhibitors will be used to examine the roles of inflammation and COX-2 in esophageal adenocarcinogenesis. 4) To develop a model for studying the progression of esophageal metaplasia to adenocarcinoma and to study its inhibition by antioxidants and NASIDs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075683-04
Application #
6350247
Study Section
Special Emphasis Panel (ZRG2-PTHB (01))
Project Start
1998-04-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2003-01-31
Support Year
4
Fiscal Year
2001
Total Cost
$255,578
Indirect Cost
Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Hao, Jing; Zhang, Bin; Liu, Ba et al. (2009) Effect of alpha-tocopherol, N-acetylcysteine and omeprazole on esophageal adenocarcinoma formation in a rat surgical model. Int J Cancer 124:1270-5
Hao, Jing; Liu, Ba; Yang, Chung S et al. (2009) Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice. BMC Gastroenterol 9:59
Chen, Xiaoxin; Qin, Rong; Liu, Ba et al. (2008) Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol 8:1
Liu, Tong; Zhang, Xinyan; So, Chi-Kwong et al. (2007) Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis 28:488-96
Chen, Xiaoxin; Wang, Su; Wu, Nan et al. (2004) Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis. Clin Cancer Res 10:6703-9
Su, Yinghao; Chen, Xiaoxin; Klein, Michael et al. (2004) Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus. Lab Invest 84:753-65
Chen, Xiaoxin; Li, Ning; Wang, Su et al. (2003) Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin. J Natl Cancer Inst 95:1053-61
Chen, Xiaoxin; Li, Ning; Wang, Su et al. (2002) Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and alpha-difluoromethylornithine on tumorigenesis in a rat surgical model. Carcinogenesis 23:2095-102
Chen, Xiaoxin; Ding, Yu; Liu, Chang-Gong et al. (2002) Overexpression of glucose-regulated protein 94 (Grp94) in esophageal adenocarcinomas of a rat surgical model and humans. Carcinogenesis 23:123-30
Chen, X; Mikhail, S S; Ding, Y W et al. (2000) Effects of vitamin E and selenium supplementation on esophageal adenocarcinogenesis in a surgical model with rats. Carcinogenesis 21:1531-6

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