Chemopreventive Efficacy of Arylalkyl Isothiocyanates and N-Acetylcysteine for Lung Tumorigenesis in Fischer Rats

Abstract

The purpose of this study is to evaluate the efficacy of three promising sulfur-containing compounds, 6-phenylhexyl isothiocyanate (PHITC), phenethyl isothiocyanate (PEITC), and N-acetylcysteine (NAC), as chemopreventive agents in a long-term bioassay for lung tumorigenesis in F344 rats. PEITC occurs as a constituent of certain cruciferous vegetables, PHITC is a synthetic homologue, and NAC is an endogenous substance. Male F344 rats were treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by s.c. injection at a dose of 1.5 mg/kg body weight three times weekly for 20 weeks. This dose regimen induced a 67% tumor incidence in the lung, a major target organ of NNK. PHITC or PEITC administered in the diet for 22 weeks, a period covering from 1 week before to 1 week after the NNK treatment, exhibited significant inhibition of lung tumorigenesis induced by NNK. The lung tumor incidences in the NNK-treated groups, fed a diet containing 4 mmol/kg (876 ppm) or 2 mmol/kg (438 ppm) PHITC, were 24 and 19% and were 9 and 17% in groups fed PEITC at concentrations of 8 mmol/kg (1304 ppm) or 4 mmol/kg (652 ppm), respectively. In contrast to isothiocyanates, NAC given in the diet at 80 mmol/kg (13056 ppm) or 40 mmol/kg (6528 ppm) exerted no inhibitory effects on the NNK-induced lung tumorigenesis. At the dose studied, NNK did not induce liver and pancreatic tumors in the treated animals, but a significant increase of nasal cavity tumor incidence was observed in the NNK-treated group. However, none of the test compounds showed any effect on the tumorigenesis in this tissue. This study demonstrated that PHITC and PEITC were potent chemopreventive agents for the NNK-induced lung tumorigenesis in F344 rats, whereas NAC was not active at all. These results support further evaluation of these compounds in chemoprevention studies.