Faculty Collaboration Database

The effects of L-748706, a selective cyclooxygenase-2 inhibitor, on N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. Carcinogenesis 2005 Sep;26(9):1590-5

Date

05/10/2005

Pubmed ID

15878914

DOI

10.1093/carcin/bgi111

Scopus ID

2-s2.0-24144451787 (requires institutional sign-in at Scopus site)   27 Citations

Abstract

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.

Author List

Stoner GD, Qin H, Chen T, Carlton PS, Rose ME, Aziz RM, Dixit R

MESH terms used to index this publication - Major topics in bold

4-Butyrolactone
Animals
Anti-Inflammatory Agents, Non-Steroidal
Carcinogens
Carcinoma, Squamous Cell
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Dimethylnitrosamine
Dinoprostone
Esophageal Neoplasms
Gene Expression Regulation, Enzymologic
Male
Piroxicam
Prostaglandin-Endoperoxide Synthases
RNA, Messenger
Rats
Rats, Inbred F344
Sulfones