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 micro mol/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 micro mol/g diet), MI (55.5 micro mol/g diet), or
PEITC-NAC plus MI (3 micro mol plus 55.5 micro mol/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.