Effect of alkyl chain length on inhibition of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis and DNA methylation by isothiocyanates

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Abstract
This study was undertaken to evaluate the inhibitory effects of benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC) or 4- phenylbutyl isothiocyanate (PBITC) on N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in male Fisher 344 rats. Groups of 15 male rats were fed modified AIN-76A diet or diet containing the four isothiocyanates at concentrations of 2.5, 1.0 and 0.4 μmol/g diet for 25 weeks. After two weeks, rats were administered 0.5 mg/kg NMBA S.C. once weekly for 15 weeks. Additional controls received modified AIN-76A diet only or diet containing the high concentration of isothiocyanates (2.5 μmol/g) only. No tumors were found in any of the groups that were not administered NMBA. Rats treated with NMBA only developed 6.7±0.8 tumors/animal. Tumor incidences in rats treated with 2.5 and 1.0 μmol PEITC/g diet, and with all three dietary concentrations of PPITC were inhibited by 60/100% compared to controls. Tumor multiplicities were inhibited by 83–100% by PEITC or PPITC at all dietary concentrations tested. PPITC clearly had a stronger inhibitory effect on NMBA tumorigenesis than did PEITC. Compared to PEITC and PPITC, BITC and PBITC had little inhibitory effect on tumor multiplicity and no effect on NMBA tumor incidence. In general, the occurrence of preneoplastic lesions (acanthoses, hyperkeratose, leukoplakias and leukokeratoses) was inhibited in a similar manner as tumor incidence and multiplicity, except that no experimental diet resulted in a significant reduction of the incidence of acanthoses and hyperkeratoses. As with their effects on tumorigenicity and formation of premalignant lesions, the inhibitory effects of the isothiocyanates on NMBA-induced DNA methylation 24 h after administration followed the order: PPITC > PEITC > PBITC > BITC.

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