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Purpose:Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is over-expressed in the stomach during H. pylori infection. Therefore, we investigated whether non-steroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide (NIM) on H. pylori-associated gastric carcinogenesis in mice. Experimental Design: C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, NIM was mixed with feed pellets and administered for the duration of the experiment. All mice were sacrificed 50 weeks after the commencement of the experiment. Histopathology, immunohistochemistry and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments using human gastric cancer cell line, AGS were also performed in order to identify mechanisms underlying cancer chemoprevention by NIM. Results: Gastric tumors developed in 68.8% of mice administered both MNU and H. pylori, whereas less than 10% developed gastric tumors when administered either MNU or H. pylori alone. These findings indicate H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, NIM administration significantly reduced H. pylori-associated gastric tumorigenesis, whereas significant inductions of apoptosis were observed. In vitro studies demonstrated that NIM and H. pylori combined acted synergistically to induce more apoptosis than either alone. Conclusions: Our data show NIM prevents H. pylori-associated gastric carcinogenesis, and suggest COX-2 may be a target for chemoprevention of gastric cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]