Effects of alkyl chain length on the inhibition of NNK-induced lung neoplasia in A/J mice by arylalkyl isothiocyanates

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Abstract
Six homologous arylalkyl isothiocyanates were evaluated for their abilities to inhibit pulmonary adenomas induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-l-(3-pyridyl)-1-butanone (NNK) in A/J mice. Four consecutive daily doses (5 μmol/mouse) of phenyl isothiocyanate (PITC), benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PETTC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC), 4-oxo-4-(3-pyridyl)-butyl isothiocyanate (OPBITC) and corn ofl were administered to mice by gavage. Two hours following the final dosing, mice were administered saline or 10 μmol of NNK in saline i.p. Pulmonary adenomas were counted at 16 weeks after NNK administration. The mice administered only corn oil prior to NNK developed an average multiplicity of 9.2 tumors/ mouse. Pretreatment with PITC, BITC and OPBITC had no significant effects on NNK-induced lung neoplasia. However, PEITC pretreatment resulted in a 64% reduction of lung tumor multiplicity, but did not affect the percentage of mice that developed tumors. Both PPITC and PBITC decreased tumor multiplicity by 96% and the percentage of tumor-bearing animals by >60%. These results, in conjunction with our previous work, demonstrate a general trend of increasing inhibition of NNK-induced lung neoplasia by arylalkyl isothiocyanates with increasing alkyl chain length. This study also demonstrates the remarkable inhibitory activities of PPITC and PBITC, two isothiocyanates that had not previously been tested as chemopreventive agents.

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