Primary Motility  Disorders of the  Esophagus
 The Esophageal
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Volume: Barrett's Esophagus
Chapter: Dysplasia

Is there a role for cyclooxygenase-2 inhibitors in the prevention of Barrett's-associated adenocarcinomas?

R.F. Souza (Dallas)

The incidence of esophageal adenocarcinoma has been increasing rapidly for more than two decades [1]. The development of esophageal adenocarcinoma proceeds in a step wise manner from chronic esophageal inflammation to carcinoma (Figure 1). Gastroesophageal reflux disease (GERD) has been established as a strong risk factor for adenocarcinoma of the esophagus [2], and more than 40% of adult Americans experience regular GERD symptoms [3]. In some individuals, the chronic esophageal inflammation induced by GERD results in intestinal metaplasia, a condition known as Barrett's esophagus (Figure 1). This metaplastic epithelium is predisposed to malignancy, and most esophageal adenocarcinomas are judged to arise from Barrett's esophagus [2, 4]. In the setting of continued injury as a result of acid reflux, this metaplastic epithelium progresses in a stepwise manner to low-grade dysplasia, high-grade dysplasia and finally carcinoma (Figure 1). With the recent advances in molecular biology, efforts to characterize the molecular events during the progression of Barrett's metaplasia to carcinoma have intensified. A greater understanding of Barrett's-associated neoplasia at the molecular level may identify targets to which chemopreventive and chemotherapeutic therapies can be directed.

Figure 1. Pathogenesis of Barrett's-associated adenocarcinomas.

Recently, interest has focused on cyclooxygenase (COX) as one such molecular target at which to direct new therapies. COXs are the key enzymes that mediate the production of prostaglandins from arachidonic acid. Two isoforms of COX have been identified, COX-1 and COX-2. COX-1 is expressed constitutively, whereas COX-2 can be induced by a number of agents including cytokines, growth factors, and tumor promoters [5-7]. Data from both human and animal studies suggest an important role for COX-2 in gastrointestinal tumorigenesis [8, 9]. Studies in vitro have shown that overexpression of COX-2 reduces the rate of apoptosis, and increases the invasiveness of malignant cells [10-13]. Up-regulation of COX-2 has been observed in a number of human tumors including colorectal, pancreatic, and gastric adenocarcinomas [14-17]. Furthermore, overexpression of COX-2 has been detected in human esophageal squamous cell carcinomas and adenocarcinomas, and in the non-malignant, metaplastic epithelium of Barrett's esophagus [18-20].

A number of epidemiologic studies have concluded that the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) which inhibit both COX-1 and COX-2 may protect against the formation of gastrointestinal tumors [21-23]. Recent data suggest that this antitumor effect may be the result of inhibition of COX-2. NSAIDs that selectively inhibit COX-2 have been shown to reduce the formation of colorectal carcinomas in animal models, to inhibit the formation of colonies by human colorectal carcinoma cell lines [24, 25], and to retard the growth of human pancreatic carcinoma cell lines [26]. COX-2 selective NSAIDs also have been shown to decrease both the number and size of colonic polyps in patients with familial adenomatous polyposis [27]. Contrasting data suggest that NSAIDs may prevent carcinogenesis through mechanisms other than COX inhibition. For example, NSAIDs which possess no COX inhibitory activity have been shown to inhibit the growth of colon tumors, both in vivo and in vitro, and to inhibit the proliferation of pancreatic carcinoma cell lines [26, 28]. Thus, it is not clear whether the antitumor effects of NSAIDs result from inhibition of COX-2, both COX-1 and COX-2, or from some COXindependent mechanism. Few data are available on the antitumor effects of NSAIDs and the mechanisms of NSAID-mediated effects in Barrett's-associated adenocarcinomas and adenocarcinoma cell lines.

Using appropriate doses of the COX-2 selective inhibitor NS-398 and the COX-1 selective inhibitor flurbiprofen, our laboratory examined the effects of selective COX-1 or COX-2 inhibition on proliferation and apoptosis in Barrett's-associated esophageal adenocarcinoma cells lines. Selective inhibition of COX-2 by NS-398 significantly decreased cell proliferation and increased apoptotic cell death in Barrett's-associated esophageal adenocarcinoma cell lines that expressed COX-2. No significant effect was seen in a cell line that did not express COX-2. Furthermore, flurbiprofen, at doses selective for COX-1, had no significant effect on proliferation in any of the Barrett's-associated adenocarcinoma cell lines. These data suggest that specific inhibition of COX-2 results in antiproliferative and pro-apoptotic effects in Barrett's-associated esophageal adenocarcinoma cell lines. Other investigators have shown that COX-2 inhibition is not the only mechanism of NSAID-mediated apoptosis in Barrett's-associated esophageal adenocarcinoma cell lines. Indomethacin, at doses that inhibit both COX-1 and COX-2, induced apoptosis in these same Barrett's-associated esophageal adenocarcinoma cell lines independent of whether the cell line expressed COX-2 or not [29]. Taken together, these results suggest that NSAIDs through COX-2 dependent and independent mechanisms may have a role in the management of Barrett's-associated adenocarcinomas. These studies provide an experimental basis for clinical studies designed to determine whether COX-2 selective or nonselective NSAIDs will be useful in the chemoprevention or treatment of adenocarcinoma in Barrett's esophagus.


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Publication date: August 2003 OESO©2015