Carcinogenesis Advance Access published online on May 5, 2005
Carcinogenesis, doi:10.1093/carcin/bgi111
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1 Cancer Chemoprevention and Support Program, Division of Hematology and Oncology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210
* To whom correspondence should be addressed. Epidemiological studies suggest that the frequent intake of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk of developing esophageal squamous cell carcinoma (SCC). This decrease is thought to correlate with the inhibition of cyclooxygenase (COX) activity. The production of prostaglandin E2 (PGE2), a major metabolite of COX, is increased in numerous human cancers including esophageal SCC, therefore, inhibition of COX activity and subsequent suppression of the formation of PGE2 may be chemopreventive in the esophagus. The objective of the present study was to determine whether L-748706 (L-706), a novel selective COX-2 inhibitor, would prevent N-Nitrosomethylbenzylamine (NMBA)-induced esophageal tumor progression in the Fischer 344 (F344) rat. In rats pretreated with a low dose of NMBA (0.25 mg/kg body weight), L-706 at 100 ppm in the diet significantly reduced tumor multiplicity but not tumor incidence. At 150 ppm in the diet, L-706 alone and in combination with 200 ppm piroxicam produced significant reductions in both tumor incidence and multiplicity. Inhibition of tumor development in low-dose NMBA-treated rats was associated with reductions in esophageal cell proliferation rates and PGE2 levels in preneoplastic tissues. In contrast, in rats treated with a higher dose of NMBA (0.5 mg/kg body weight), neither L-706 alone nor in combination with piroxicam reduced esophageal tumor incidence or multiplicity in spite of the fact that they reduced esophageal PGE2 levels in preneoplastic tissues and in papillomas. Cell proliferation rates were reduced only in animals treated with L-706 + piroxicam. Our data suggest that the chemopreventive treatments were effective in inhibiting tumor development in NMBA-treated animals only when they reduced PGE2 levels in preneoplastic esophageal tissues approximately to those levels found in normal esophagus.
Received January 26, 2005
Revised April 18, 2005
Accepted April 26, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
The effects of L-748706, a selective cyclooxygenase-2 inhibitor, on N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis
2 Merck Research Laboratories, West Point, Pennsylvania 19486
Gary D. Stoner, E-mail: stoner.21{at}osu.edu
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