COX Inhibition Shows Efficacy in Oral Cancer Chemoprevention

IITRI Displays Data at AACR Meeting

Identification of differentially expressed genes in sitespecific neoplasms provides a mechanism-based approach to agent selection for cancer chemoprevention.

IITRI displayed study results on this topic in a poster presentation at the American Association for Cancer Research (AACR) meeting April 6-10 in San Francisco, CA. The study was co-authored by IITRI scientists Jonathan Phillips, Thomas Horn, William Johnson and David McCormick, and was supported by a division of the National Cancer Institute.

In the study, PCR techniques were used to quantify the expression of a small battery of genes that were considered possible mechanistic targets for oral cancer prevention. The scientists identified one gene (cyclooxygenase-2 [COX-2]) that is highly overexpressed in oral cancers induced by NQO.

They also demonstrated that dietary administration of a specific COX- 2 inhibitor (celecoxib) and an agent that inhibits both COX-1 and COX-2 (piroxicam) both confer protection against oral carcinogenesis in the rat/ NQO model system.

Based on results of this study, the following conclusions were drawn:

1. Demonstration of COX-2 overexpression in oral cancers induced by NQO identified COX-2 as a potentially viable target for oral cancer chemoprevention. These results clearly suggest that COX-2 inhibitors may be effective in cancer prevention in this site.

2. PCR data from the present study do not support a logical mechanistic rationale to study inhibitors of EGFR, PPAR?, or 12-LOX as chemopreventive agents for oral cancer induced by NQO.

3. The efficacy of COX inhibition predicted on the basis of molecular biology results was confirmed in the oral cancer chemoprevention study: dietary administration of a specific COX-2 inhibitor (celecoxib) and a non-specific COX inhibitor (piroxicam): reduced oral cancer incidence, reduced the invasiveness of induced cancers, and reduced cancerassociated mortality.

4. All mortality occurring after study week 10 was cancer-related; COX inhibition by celecoxib or piroxicam resulted in statistically significant reductions in cancer-related mortality.

5. Body weight loss was a strong predictor of cancer-associated mortality. Reductions in mean body weight observed in the dietary control group after week 20 were largely prevented by dietary administration of either celecoxib or piroxicam.

6. The results of the present studies accomplish the following:

• confirm the utility of the NQO model for preclinical evaluation of novel agents for the prevention of oral cancer
• demonstrate the utility of applying alterations in gene expression to the identification of cancer chemopreventive agents
• and suggest that COX inhibition may provide a viable strategy for the prevention of oral cancer in humans