Oral squamous cell carcinomas induced in rats by
4-nitroquinoline-1-oxide (NQO) show substantial overexpression of
cyclooxygenase-2 (COX-2) when compared with adjacent phenotypically normal oral tissues. By contrast, neither
5-lipoxygenase (LOX) nor 12-LOX is overexpressed in rat
oral cancers. Two
chemoprevention studies were done to test the resulting hypothesis that COX-2 is a useful target for
oral cancer chemoprevention in the rat. In both studies, male F344 rats received
drinking water exposure to NQO (20 ppm) for 10 weeks, followed by administration of chemopreventive agents from week 10 until study termination at week 26. In the first study, groups of rats were fed basal diet (control), or basal diet supplemented with the selective
COX-2 inhibitor celecoxib (500 or 1,500 mg/kg diet), the nonselective COX inhibitor
piroxicam (50 or 150 mg/kg diet), or the 5-LOX inhibitor
zileuton (2,000 mg/kg diet). In the second study, rats were fed basal diet (control) or basal diet supplemented with
nitric oxide-naproxen (180 or 90 mg/kg diet), a nonselective COX inhibitor that shows reduced gastrointestinal toxicity. When compared with dietary controls,
celecoxib decreased
oral cancer incidence,
cancer invasion score, and
cancer-related mortality.
Piroxicam decreased
cancer-related mortality and
cancer invasion score, whereas
nitric oxide-naproxen decreased
oral cancer incidence and
cancer invasion score. By contrast,
zileuton showed no chemopreventive activity by any parameter assessed. These data show that both selective and nonselective inhibitors of COX-2 can prevent NQO-induced oral
carcinogenesis in rats. The chemopreventive activity of COX inhibitors may be linked to overexpression of their enzymatic target in incipient
oral neoplasms.