Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398

Acetylsalicylic acid (ASA) is known to prevent cancer development, but its mechanism of action remains unclear. In this study, we compared the efficac ies of this nonspecific cyclooxygenase (COX) inhibitor with N-[2-(cyclohexy loxy)-4-nitrophcnyl]-methanesulfonamide (NS-398), a specific COX-2 inhibito r. COX-2-specific inhibitors are less toxic than ASA. Lung tumorigenesis wa s induced in A/J mice by the administration of the tobacco-specific nitrosa mine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the drinking w afer for 7 weeks (weeks 0 to +7). Groups of 25 A/J mice were fed ASA (588, 294, 147, or 73 mg/kg diet) before and throughout the assay (weeks -2 to +2 3), ASA at a dose of 588 mg/kg diet was the most effective because it reduc ed lung tumor multiplicity by 53%. The preventive effect of ASA increased w ith the dose, being of 32, 30, and 44% for 73, 147, and 294 mg/kg diet, res pectively. NNK increased plasma prostaglandin E-2 (PGE(2)) basal levels by 413%, whereas ASA attenuated this elevation in a dose-response manner (r(2) = 0.99). Plasma PGE(2) levels in ASA + NNK-treated mice correlate with the logarithm of the number of tumors (r(2) = 0.99). NS-398 inhibited lung tum or multiplicity by 34% and returned plasma PGE, to basal levels observed in untreated mice,among the NNK-exposed mice, ASA and NS-398 treatment decrea sed the mean of the lung tumor volumes. Incubation of 82-132 and LM2 murine lung tumor cells with ASA or NS-398 decreased cell proliferation by 50% at concentrations higher than 100 mu M. Incubations of NNK with COX-1 and -2 produced both activation and detoxification products by cu-carbon hydroxyla tion and N-oxydation pathways, respectively. Bioactivation of NNK was more extensive by COX-2 than COX-I. Anti-COX-1 and -2, arachidonic acid, ASA, an d NS-398 inhibited NNK bioactivation by COX-1 and -2 from 22-49%. Our data suggest that NNK is bioactivated by COX-2 in lung tissues and that COX-2-sp ecific inhibitors might be promising chemopreventive agents.