The purpose of this investigation was to establish a dose response for the effects of dietary
phenethyl isothiocyanate (
PEITC) on
N-nitrosomethylbenzylamine (NMBA)-induced esophageal
tumorigenesis and DNA methylation. Groups of 13-27 rats were randomly assigned to AIN-76A diets containing 0, 0.325, 0.75, 1.5 or 3.0 mumol
PEITC/g. Two weeks later, rats were administered NMBA subcutaneously at a dose of 0.5 mg/kg once a week for 15 weeks. Animals were maintained on control or experimental diets for an additional 8 weeks and were terminated at week 25 of the experiment. No significant effects on
weight gain or food intake were noted for any of the experimental diets when compared with control values. Animals receiving only NMBA developed 9.3 +/- 0.9
tumors/rat, with an incidence of 100%. Dietary
PEITC at concentrations of 0.75, 1.5 and 3.0 mumol/g inhibited NMBA-induced esophageal
tumor multiplicity by 39%, 90% and 100%, respectively. Esophageal
tumor incidence in these groups was reduced by 0%, 40% and 100%, respectively. The 0.325 mumol/g
PEITC diet did not significantly affect NMBA-induced esophageal
tumorigenesis. These results indicate that the minimum inhibitory dietary concentration of
PEITC is between 0.325 and 0.75 mumol/g. Groups of 20 rats were assigned to diets containing 0-3.0 mumol
PEITC/g for two weeks as described above, and then sacrificed 24 hours after administration of [3H-methyl]NMBA. The esophageal
DNA was isolated, purified, hydrolyzed, and analyzed by HPLC.
PEITC inhibited DNA methylation in a dose-dependent manner, as was found in the
tumor bioassay. The inhibition of
tumor incidence was highly correlated with the percentage inhibition of either
7-methylguanine or
O6-methylguanine. These latter results suggest that the inhibitory activity of
PEITC in this model is manifested, at least in part, during the functional equivalent of
tumor initiation.