Chemoprevention of esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, and to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.

Figure 1

Structures of some esophageal carcinogens (from Stoner and Gupta, 2001).

Figure 2

Schema for metabolic activation of NMBA (from Stoner and Gupta, 2001).

Figure 3

Appearance of rat esophageal lesions at the termination of a 25-wk bioassay. There are several papillomas on the surface of the esophagus. The lesion on the lower left was found to be a carcinoma upon histological analysis (from Stoner et al., 2006).

Figure 4

Histopathology of NMBA-induced lesions in rat esophagus (from Stoner et al., 2006).

Figure 5

Molecular events in papilloma development during NMBA-induced rat esophageal tumorigenesis (from Stoner and Gupta, 2001).

Figure 6

Structures of isothiocyanates (from Stoner and Gupta, 2001).