Journal Article

Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and α-difluoromethylornithine on tumorigenesis in a rat surgical model

Xiaoxin Chen, Ning Li, Su Wang, Jungil Hong, Mingzhu Fang, Joseph Yousselfson, Peiying Yang, Robert A. Newman, Ronald A. Lubet and Chung S. Yang

in Carcinogenesis

Volume 23, issue 12, pages 2095-2102
Published in print December 2002 | ISSN: 0143-3334
Published online December 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.12.2095
Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and α-difluoromethylornithine on tumorigenesis in a rat surgical model

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

Human esophageal adenocarcinoma (EAC) develops in a sequence from gastroesophageal reflux disease (GERD), columnar-lined esophagus (CLE), dysplasia, and eventually to EAC. We established a rat surgical EAC model with esophagogastroduodenal anastomosis (EGDA) to mimic the staged process of esophageal adenocarcinogenesis. Profiling of the AA metabolites with mass spectrometry showed that prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 15-hydroeicosatetraenoic acid (HETE), 12-HETE, 8-HETE and 5-HETE all increased at the esophagoduodenal junction after EGDA as compared with the proximal esophagus, with PGE2 as the major metabolite. Consistent with this profile, cyclooxygenase 2 (Cox2) was overexpressed in the basal cell layer of esophageal squamous epithelium, CLE cells and EAC tumor cells of the EGDA rats, as compared with the normal esophageal epithelium. Sulindac (a Cox inhibitor), nordihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) and α-difluoromethylornithine (DFMO, an ornithine decarboxylase inhibitor) were tested for their possible inhibitory actions against the formation of EAC in the rat EGDA model. In a short-term study (for 4 weeks after surgery), dietary administration of both sulindac (300 and 600 p.p.m.) and NDGA (100 p.p.m.) effectively reduced the EGDA-induced inflammation. In a long-term chemoprevention study (for 40 weeks after surgery), 300 p.p.m. sulindac, alone or in combination with 100 p.p.m. NDGA or 0.5% DFMO, decreased the tumor incidence from 57.7 to 26.9%, or 16.7 or 20%, respectively (P < 0.05). NDGA alone (100 and 200 p.p.m.) slightly decreased the tumor incidence to 52.4 and 37%, respectively, although the difference was not statistically significant. DFMO alone did not show significant effects on tumor incidence. Inhibition of tumor formation by sulindac was correlated with lowered levels of PGE2. In conclusion, sulindac exerted its chemopreventive effect against the formation of EAC in the rat EGDA model possibly through its inhibition of Cox.

Keywords: AA, arachidonic acid; CLE, columnar-lined esophagus; Cox, cyclooxygenase; DFMO, α-difluoromethylornithine; EAC, esophageal adenocarcinoma; EGDA, esophagogastroduodenal anastomosis; EIA, enzyme immunoassay; ESCC, esophageal squamous cell carcinoma; FAP, familial adenomatous polyposis; GERD, gastroesophageal reflux disease; HETE, hydroeicosatetraenoic acid; LC/MS/MS, high performance liquid chromatography/electrospray ionization tandem mass spectrometry; Lox, lipoxygenase; LTB4, leukotriene B4; NDGA, nordihydroguaiaretic acid; NSAIDs, non-steroidal anti-inflammatory drugs; ODC, ornithine decarboxylase; PGE2, prostaglandin E2

Journal Article.  7319 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.