Epidemiological studies indicate an association between the frequent use of nonsteroidal anti-inflammatory drugs and decreased risk for
esophageal cancer. These studies suggest that limiting excess
prostaglandin production, via inhibition of
cyclooxygenase (COX)-mediated
arachidonic acid metabolism, may be an important strategy for the prevention of this type of
malignancy.
N-Nitrosomethylbenzylamine (NMBA)-induced
tumorigenesis in the rat esophagus is a model of human
esophageal squamous cell carcinoma used for investigations of chemical
carcinogenesis and for the evaluation of putative chemopreventive agents. In this study, we characterized COX-mediated
arachidonic acid metabolism in NMBA-induced rat esophageal
tumorigenesis by measuring COX-1 and COX-2 expression and
prostaglandin E(2) production. In addition, we evaluated the ability of
piroxicam, a potent COX inhibitor, to prevent postinitiation events of NMBA-induced
tumorigenesis in the rat esophagus. After a 2-week acclimatization period, groups of 30 male F344 rats received s.c.
injections of NMBA (0.5 mg/kg b.w.) three times/week for 5 weeks. Seventy-two h after the final NMBA treatment and for the remainder of the study,
piroxicam was administered in the diet at 200 and 400 ppm. Twenty-five weeks after the initiation of NMBA treatment, we observed an elevation in COX
mRNA and
protein expression and
prostaglandin E(2) production in NMBA-treated esophageal tissues compared with normal epithelium. However, these changes were associated with data indicating that a COX inhibitor is not preventive in NMBA-induced rat esophageal
tumorigenesis. Administration of
piroxicam in the diet produced no significant reductions in esophageal
tumor incidence, multiplicity, or size. The reasons for the lack of effect are largely unknown but may be related to the inability of
piroxicam to modulate other biochemical pathways involved in NMBA-induced
tumorigenesis.