Chemoprevention of esophageal cancer: Investigation of inducible nitric oxide synthase as a chemopreventive target in N-nitrosomethylbenzylamine-induced esophageal tumorigenesis.

摘要

Esophageal cancer is the third most common gastrointestinal malignancy and is the sixth most frequent cause of cancer death in the world. Estimates of cancer incidence in the United States for 2003 indicate that 13,900 citizens will be diagnosed with esophageal cancer. It is usually discovered at an advanced stage and becomes to fatal rapidly. One-year and 5-year survival rates for esophagus cancer are very low. Seventy-five percent of untreated patients with esophagus cancer die within 1 year of diagnosis and 5-year survival rates are only 5–10%. The N-nitrosomethylbenzylamine (NMBA)-induced rat model of esophageal cancer has been used extensively in our laboratory to investigate the mechanisms of tumor development in the esophagus and to evaluate the efficacy of potential chemopreventive agents including whole food and a variety of single agents. Our investigations provide experimental support for chemoprevention trials of esophageal cancer in humans.; Nitric oxide (NO) is a single molecular and a high level of NO is synthesized from L-arginine by inducible nitric oxide synthase (iNOS). Increased NO production appears to be associated with many disorders including cancer. Therefore, as shown in many studies, iNOS plays a very important role in carcinogenesis. To investigate the association between iNOS and tumor development in rat esophagus, we conducted a bioassay in which rats were sacrificed at three-week intervals during and following expose to NMBA. Real-time PCR and immunohistochemistry assays have been used to determine mRNA and protein expression of NOS. The results of this study suggest that overexpression of iNOS is associated with tumor development in the rat esophagus. Based on our findings, we conducted a second bioassay to evaluate a selective iNOS inhibitor, PBIT, and black raspberries as chemopreventive agents targeting the function of iNOS. We observed a statistically significant reduction in tumor incidence and multiplicity in rats fed with PBIT or black raspberries when compared to rats fed with regular diet only. In summary, our data indicate that iNOS plays an important role in esophageal cancer and its inhibitor(s) might be potential chemopreventive agents in esophageal cancer in humans.