Chemopreventive efficacies of aspirin and sulindac against lung tumorigenesis in A/J mice.
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs. In this study, we demonstrated the efficacy of aspirin to inhibit lung tumorigenesis in A/J mice. Lung tumors (9.9 tumors/mouse) were induced by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), administered in drinking water between week 0 and week +7. Groups of mice were fed sulindac (123 mg/kg diet), acetylsalicylic acid (ASA; 294 mg/kg), non-buffered Aspirin (294 mg/kg) or buffered Aspirin (294 mg/kg) in AIN-76A diet from week -2 to the end of the bioassay (week +23). These doses are comparable to the maximal doses recommended for humans. ASA and non-buffered Aspirin were the most effective inhibitors and reduced lung multiplicities by 60 and 62%, respectively. Sulindac inhibited lung tumor multiplicity by 52%. Inhibition by buffered Aspirin was not statistically significant. We evaluated the efficacies of NSAIDs to inhibit NNK activation by h1A2 v2 cells expressing human P-450 1A2. Salicylates, at doses of 500 microM and 1 mM, had no effect on NNK activation. Sulindac and its sulfide and sulfone metabolites (1 mM) inhibited NNK metabolism by 90, 92 and 65%, respectively. We observed a 76% inhibition with SKF 525A, a P-450 inhibitor. Taken together, these results indicate that salicylates and sulindac could be equally effective as chemopreventive agents, but they could differ in their mode of action.
Duperron
C
C
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
Castonguay
A
A
D000236:Adenoma / Q000139:chemically induced*; D000818:Animals; D001241:Aspirin / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced*; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000378:metabolism*; D011355:Prodrugs / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology*
D009602:Nitrosamines; D011355:Prodrugs; D013467:Sulindac; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D019388:Cytochrome P-450 CYP1A2; D001241:Aspirin