Journal Article

Inhibition of lung tumorigenesis in A/J mice by <i>N</i>-acetyl-<i>S</i>-(<i>N</i>-2-phenethylthiocarbamoyl)-L-cysteine and <i>myo</i>-inositol, individually and in combination

Stephen S. Hecht, Pramod Upadhyaya, Mingyao Wang, Robin L. Bliss, Edward J. McIntee and Patrick M.J. Kenney

in Carcinogenesis

Volume 23, issue 9, pages 1455-1461
Published in print September 2002 | ISSN: 0143-3334
Published online September 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.9.1455
Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination

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Isothiocyanates, their N-acetylcysteine conjugates, and myo-inositol (MI) are inhibitors of lung tumorigenesis in A/J mice. However, chemoprevention by combinations of these compounds in different temporal sequences has not been examined. This is important for developing practical approaches to lung cancer chemoprevention in smokers and ex-smokers. We used a tumor model in which A/J mice are treated with 8 weekly doses of benzo[a]pyrene (B[a]P) plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and killed 19 weeks after the final treatment. In Experiment 1, isothiocyanates or their N-acetylcysteine conjugates were added to the diet (1 or 3 μmol/g) from 1 week before until 1 week after carcinogen treatment. The compounds were 2-phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), N-acetyl-S-(N-benzyl-thiocarbamoyl)-L-cysteine (BITC-NAC), N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine (PEITC-NAC), and N-acetyl-S-(N-3-phenylpropylthiocarbamoyl)-L-cysteine (PPITC-NAC). Significant reductions in lung tumor multiplicity were observed in mice treated with PEITC, PEITC-NAC, PPITC and PPITC-NAC. PEITC-NAC was chosen for combination studies with MI (Experiment 2). Mice were treated with B[a]P plus NNK without or with PEITC-NAC (3 μmol/g diet), MI (55.5 μmol/g diet), or PEITC-NAC plus MI (3 μmol plus 55.5 μmol/g diet). Different temporal sequences of dietary additions were investigated: carcinogen treatment phase; post-carcinogen treatment phase; entire experiment; 50% of carcinogen treatment phase until termination; and 75% of carcinogen treatment phase until termination. All treatments reduced lung tumor multiplicity except PEITC-NAC post-carcinogen or from 75% of the carcinogen treatment phase. Reduction of lung tumor multiplicity by PEITC-NAC plus MI was greater than that in the mice treated with the agents alone in all temporal sequences. When all results were combined, PEITC-NAC plus MI was significantly more effective than the agents alone. There was a significant trend for reduction in lung tumor multiplicity with increased duration of treatment by the chemopreventive agents. These results provide a basis for further development of mixtures of PEITC-NAC and MI for chemoprevention of lung cancer.

Keywords: BaP, benzo[a]pyrene; BITC, benzyl isothiocyanate; BITC-NAC, N-acetyl-S-(N-benzylthiocarbamoyl)-l-cysteine; MI, myo-inositol; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PEITC, 2-phenethyl isothiocyanate; PEITC-NAC, N-acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine; PPITC, 3-phenylpropyl isothiocyanate; PPITC-NAC, N-acetyl-S-(N-3-phenylpropylthiocarbamoyl)-l-cysteine

Journal Article.  5459 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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