Journal Article

The effects of L-748706, a selective cyclooxygenase-2 inhibitor, on <i>N</i>-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis

Gary D. Stoner, Haiyan Qin, Tong Chen, Peter S. Carlton, Miranda E. Rose, Robeena M. Aziz and Rakesh Dixit

in Carcinogenesis

Volume 26, issue 9, pages 1590-1595
Published in print September 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi111
The effects of L-748706, a selective cyclooxygenase-2 inhibitor, on N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis

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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 p.p.m. in the diet significantly reduced tumor multiplicity but not tumor incidence. At 150 p.p.m. in the diet, L-706 alone and in combination with 200 p.p.m. 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.

Keywords: COX, cyclooxygenase; iNOS, nitric oxide synthase; LIs, labeling indices; NMBA, N-nitrosomethylbenzylamine; NSAIDs, non-steroidal anti-inflammatory drugs; PBIT, S,S′-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (dihydrobromide); PCNA, proliferating cell nuclear antigen; PGE2, prostaglandin E2; SCC, squamous cell carcinoma

Journal Article.  5143 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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