N-Acetyl-S and Lung Tumors (mice)

Effects of N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine (PEITC-NAC) and myo-inositol (MI), individually and in combination, on lung tumorigenesis in A/J mice treated with benzo[a]pyrene (BaP) plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

Stephen S. Hecht, Pramod Upadhyaya, Patrick M. J. Kenney, Edward J. McIntee, Mingyao Wang

University of Minnesota Cancer Center, Minneapolis, MN.

Effective chemopreventive agents against smoking-induced lung cancer are urgently needed. In previous studies, we have shown that both 2-phenethyl isothiocyanate (PEITC) and MI decrease lung tumor multiplicity in A/J mice treated with a mixture of BaP and NNK, two important lung carcinogens in tobacco smoke.

In this study, we investigated the effects of PEITC-NAC, MI and PEITC-NAC plus MI on induction of lung tumors by BaP plus NNK. PEITC-NAC was selected based on the results of a preliminary study in which we evaluated the efficacy of several isothiocyanates and their N-acetylcysteine conjugates during the carcinogen treatment phase.

The design of the main experiment was as follows. Groups of 20 female A/J mice were treated once weekly for 8 weeks by gavage with a mixture of BaP plus NNK (3 ìmol each) and sacrificed 19 weeks after the last carcinogen treatment. PEITC-NAC (978 ppm), MI (10,000 ppm), or PEITC-NAC plus MI (978 and 10,000 ppm) were added to AIN-93 diet at different intervals as follows: entire carcinogen treatment period, post-carcinogen treatment period only, entire experiment, from week 4 of carcinogen treatment until termination, and from week 6 of carcinogen treatment until termination. Statistically significant reductions (26-65%) in lung tumor multiplicity were observed in all groups except MI given during carcinogen treatment, PEITC-NAC given post-carcinogen treatment, and PEITC-NAC given from week 6 of carcinogen treatment.

There were no effects on forestomach tumor multiplicity. Reduction in lung tumor multiplicity was significantly related to length of treatment with all agents. In each treatment period, inhibition by PEITC-NAC plus MI was greater than achieved by the compounds alone, and when lung tumor data from all groups were combined, the combination of PEITC-NAC plus MI was significantly more effective than either agent alone.

These results provide a basis for further exploration of chemoprevention of lung cancer by a combination of PEITC-NAC and MI.

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