Investigations in this collaborative chemoprevention project have clearly demonstrated that arylalkyl isothiocyanates, both naturally-occurring and synthetic, are potent inhibitors of nitrosamine carcinogenesis. Initially, phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, was shown to inhibit the induction of lung tumors in F-344 rats by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Metabolic studies using explant cultures of rat and human lung tissue indicated that PEITC inhibits the conversion of NNK to metabolites that elicit DNA damage. Recently, PEITC was found to be a potent inhibitor of N-nitrosobenzylmethylamine (NBMA)-induced esophageal tumors in F-344 rats. When given in the diet at concentrations of 3 and 6 mumol/g, PEITC inhibited NBMA esophageal tumorigenesis by 99-100%. Based, in part, upon these observations we propose the following objectives for this renewal: (1) To compare the abilities of PEITC, 6-phenylhexyl isothiocyanate (PHITC), and benzyl isothiocyanate (BITC) to inhibit esophageal tumorigenesis in rats by NBMA; (2) In collaboration with Program 3, to investigate the effects of these isothiocyanates on NBMA metabolism by esophageal microsomes; (3) To determine the mechanism(s) of PEITC enhancement of NBMA tumorigenesis in the rat esophagus when administered at a low dose in the diet; (4) To compare the abilities of PEITC, PHITC, and BITC to inhibit the metabolism of NNK in cultured human lung tissue; (5) To investigate the metabolism of PEITC and PHITC in cultured human lung tissue; (6) To conduct toxicity studies of PEITC and PHITC in rats; and, (7) To investigate the mechanism(s) of PHITC toxicity to rat cecal epithelial cells.
