| Human esophageal cancer which occurs worldwide has the greatest geographic variation of many types of cancers, and falls into two major categories: the cancer is associated with tobacco and alcohol and those occurring in populations with poor nutritional diet. Our laboratory has conducted a variety of studies assessing the chemopreventive potential of many single agents, including synthetic analogues, food-derived, and conjugated isothiocyanate compounds, in the esophageal cancer animal model. We conducted two independent studies which indicated that 6-phenylhexyl isothocyanate (PHITC) may play an important role during tumor promotion/progression in nitrosamine-induced rat esophageal tumorigenesis. Based on these findings, we further conducted an additional study that evaluated the promotional activity of PHITC by the use of subcarcinogenic or near subcarcinogenic doses of N-nitrosomethylbenzylamine (NMBA). The results of the study suggest that the observed PHITC-induced enhancement of esophageal tumorigenesis may be due to mechanistic activities other than promotional effects. While PHITC had shown I adverse effects in the rat esophageal model, previous studies involving naturally occurring, synthetic, and conjugated isothiocyanates have shown that they are effective inhibitors of chemically-induced carcinogenesis. Therefore, we decided to investigate the comparative inhibitory effects of phenethyl (PEITC) and phenylpropyl (PPITC) isothiocyanates with those of their N-acetyleysteine (NAC) conjugates, PEITC-NAC and PPITC-NAC on N'-nitrosonomicotine-induced (NNN) esophageal carcinogenesis and characterize their effects on various phase I and phase II enzymes. The results indicated that ITCs and the conjugates had no significant effects on adduct levels, nor were there any differences between ITCs and their respective conjugates. However, we were able to show some modulation of gene expression at the mRNA level for a panel of phase I and phase II enzymes, thus supporting an effect of ITCs and their conjugates on xenobiotic metabolism. Finally, we decided to compare the toxicity differences between PEITC and PPITC in tumorigenic rat esophageal cell lines. The results indicated that there was a difference between the two isothiocyanates, yet the reasons for the difference in toxicity are not apparent. Thus, the overall results indicate that isothiocyanates are capable of generating different biological properties within model systems. |
