INHIBITION OF NNK-INDUCED LUNG TUMORIGENESIS BY MODULATORS OF NNK ACTIVATION

NNK, a tobacco-specific nitrosamine, is a potent lung carcinogen in A/ J nice. One Possible mechanism of reducing NNK-induced lung tumorigene sis is decreased delivery of NNK to lung as a result of enhanced hepat ic CYP activity. Pretreatment with I3C, a known CYP inducer, results i n inhibition of tumor multiplicity, decreased DNA adducts in lung, and increased DNA adducts in liver, due to induction of hepatic activatio n of NNK. A more preferable means of inhibition of NNK tumorigenesis i nvolves direct inhibition of CYP enzymes responsible for NNK activatio n in lung. The arylalkyl isothiocyanates PEITC, PPITC, PBITC, PPeITC, and PHITC are effective inhibitors of NNK-induced lung tumorigenicity and DNA adduction. PEITC inhibits NNK-induced lung tumors at a dose of 5 mu mol/day, but not at doses of 1 or 0.2 mu mol/day. PPITC, PBITC, PPeITC, and PHITC are considerably more potent inhibitors than PEITC, resulting in significant reductions in tumor multiplicity at doses of 0.2 mu mol/day. For these compounds, there is a good correlation Betwe en inhibition of tumor multiplicity and inhibition of pulmonary O-6-me thylguanine. LIM, previously shown by Wattenberg to be an effective in hibitor of NNK-induced lung tumors, and other monoterpenes are good in hibitors of NNK activation in vitro or in vivo. Thus, compounds that m odulate the metabolic activation of NNK can be potent inhibitors of NN K tumorigenesis.