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[Cancer Research 58, 5354-5360, December 1, 1998]
© 1998 American Association for Cancer Research
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Prevention of NNK-induced Lung Tumorigenesis in A/J Mice by Acetylsalicylic Acid and NS-3981

Nathalie Rioux and Andre Castonguay2

Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada, G1K 7P4

Acetylsalicylic acid (ASA) is known to prevent cancer development, but its mechanism of action remains unclear. In this study, we compared the efficacies of this nonspecific cyclooxygenase (COX) inhibitor with N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398), a specific COX-2 inhibitor. COX-2-specific inhibitors are less toxic than ASA. Lung tumorigenesis was induced in A/J mice by the administration of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the drinking water 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 +23). ASA at a dose of 588 mg/kg diet was the most effective because it reduced lung tumor multiplicity by 53%. The preventive effect of ASA increased with the dose, being of 32, 30, and 44% for 73, 147, and 294 mg/kg diet, respectively. NNK increased plasma prostaglandin E2 (PGE2) basal levels by 413%, whereas ASA attenuated this elevation in a dose-response manner (r2 = 0.99). Plasma PGE2 levels in ASA + NNK-treated mice correlate with the logarithm of the number of tumors (r2 = 0.99). NS-398 inhibited lung tumor multiplicity by 34% and returned plasma PGE2 to basal levels observed in untreated mice. Among the NNK-exposed mice, ASA and NS-398 treatment decreased 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 µM. Incubations of NNK with COX-1 and -2 produced both activation and detoxification products by {alpha}-carbon hydroxylation and N-oxydation pathways, respectively. Bioactivation of NNK was more extensive by COX-2 than COX-1. Anti-COX-1 and -2, arachidonic acid, ASA, and 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-specific inhibitors might be promising chemopreventive agents.

1 Supported by a grant from The Cancer Research Society (Canada).

2 To whom requests for reprints should be addressed, at Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada, G1K 7P4. Phone: (418) 656-2131 ext. 3182; Fax: (418) 656-2305; E-mail: Andre.Castonguay@pha.ulaval.ca.

Received 2/13/98. Accepted 10/ 2/98.




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