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.