Clinical models of chemoprevention for the esophagus

Esophageal SCC is a complex disease involving multiple etiologic factors. A number of preventive approaches could be taken to reduce the occurrence of the disease including changes in lifestyle and improved nutrition, for example, the inclusion of higher quantities of fruits and vegetables in the diet. Unfortunately, these primary prevention approaches are not easily implemented and often fall short in achieving marked reductions in disease occurrence. Chemoprevention offers another approach to reducing the risk of esophageal SCC that is likely to be useful, even though the clinical trials to date have not resulted in the identification of agents that produce marked inhibitory effects on the development of the disease. Given esophageal SCC's complex etiology, it would appear that the most effective chemoprevention strategy would be to employ agents that reduce mutational events associated with exposure to esophageal carcinogens in combination with agents that inhibit the progression of epithelial dysplasia to esophageal SCC. The feasibility of addressing carcinogen-induced mutational events is underscored by the fact that many of the suspected esophageal carcinogens are known, and inhibitors of these carcinogens have been identified in animal model systems. In addition, biomarkers to assess the efficacy of anti-initiation agents, such as levels of phase I and II enzyme activities and of carcinogen: DNA adducts, can be measured. The identification of agents that inhibit the progression of dysplastic lesions to esophageal SCC has proven difficult; however, the results of the trial with ATB and retinamide are encouraging. Clearly, it seems important to identify the active chemopreventives in the antitumor-B herbal mixture. Further studies to identify strong inhibitors of tumor progression in the rat model for esophageal SCC are also needed. Biomarkers of cell proliferation (e.g., PCNA, Ki67), cell differentiation (keratins), apoptosis, gene expression (EGFR, cyclin D1, p53), and nuclear/nucleolar morphometry can be used in studies to assess the efficacy of chemopreventives to either reverse esophageal dysplastic lesions or slow their rate of progression. The development of viable approaches toward the chemoprevention. of esophageal SCC is truly an important goal in view of the poor prognosis of this disease.