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Barrett's esophagus is a premalignant condition arising in response to chronic reflux esophagitis. Inducible nitric oxide synthase (iNOS; NOS-2) and cyclooxygenase-2 (COX-2) are mediators of inflammation and regulators of epithelial cell growth. Expression levels of iNOS and COX-2 are high in colorectal adenomas and carcinomas, and COX-2 expression is elevated in gastric cancers. To determine the involvement of iNOS and COX-2 in Barrett's-associated neoplasia, we measured expression of these genes in metaplastic Barrett's and esophageal adenocarcinomas. We detected elevated iNOS and COX-2 mRNA levels in Barrett's mucosa compared with paired gastric control tissues in 16 of 21 (76%) and 17 of 21 (80%) patients, respectively (P < 0.001 for both genes). In esophageal adenocarcinomas, iNOS and COX-2 mRNA levels were increased in four of five and five of five cases, respectively. Furthermore, in 10 of 10 Barrett's patients, immunohistochemical staining for iNOS and COX-2 expression was strongly positive and higher than in matched gastric controls. Increased COX-2 expression was confirmed by Western blotting. These findings support the hypothesis that iNOS and COX-2 are involved early and often in Barrett's-associated neoplastic progression.