title: Modulation by aspirin and naproxen of nucleotide alterations and tumors in the lung of mice exposed to environmental cigarette smoke since birth.
abstract: Chemoprevention provides an important strategy for cancer control in passive smokers. Due to the crucial role played by smoke-related chronic inflammation in lung carcinogenesis, of special interest are extensively used pharmacological agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs). We evaluated the ability of aspirin and naproxen, inhibitors of both cyclooxygenase-1 and cyclooxygenase -2, to modulate environmental cigarette smoke (ECS)-induced lung carcinogenesis in A/J mice of both genders. Based on a subchronic toxicity study in 180 postweaning mice, we used 1600 mg/kg diet aspirin and 320 mg/kg diet naproxen. In the tumor chemoprevention study, using 320 mice, exposure to ECS started soon after birth and administration of NSAIDs started after weaning. At 10 weeks of life, the NSAIDs did not affect the presence of occult blood in feces. As assessed in a subset of 40 mice, bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine levels were considerably increased in ECS-exposed mice and, irrespective of gender, both NSAIDs remarkably inhibited these nucleotide alterations. After exposure for 4 months followed by 5 months in filtered air, ECS induced a significant increase in the yield of surface lung tumors, the 43.7% of which were adenomas and the 56.3% were adenocarcinomas. Oct-4 (octamer-binding transcription factor 4), a marker of cell stemness, was detected in some adenocarcinoma cells. The NAIDs attenuated the yield of lung tumors, but prevention of ECS-induced lung adenomas was statistically significant only in female mice treated with aspirin, which supports a role for estrogens in ECS-related lung carcinogenesis and highlights the antiestrogenic properties of NSAIDs.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: La Maestra
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Agostini
authors.forename: Alberto
authors.initials: A
authors.lastname: Izzotti
authors.forename: Rosanna T
authors.initials: RT
authors.lastname: Micale
authors.affiliation: Department of Surgical and Diagnostic Sciences, University of Genoa, 16132 Genoa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.forename: Anna
authors.initials: A
authors.lastname: Camoirano
authors.affiliation: National Center of Oncology, Sofia 1756, Bulgaria.
authors.forename: Roumen
authors.initials: R
authors.lastname: Balansky
authors.affiliation: National Food Safety Toxicological Center, Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Trosko
authors.affiliation: National Cancer Institute, Division of Cancer Prevention, Chemopreventive Agent Development Research Group, Bethesda, MD 20892, USA.
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical; D005260:Female; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009288:Naproxen / Q000494:pharmacology* / Q000633:toxicity; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D016588:Anticarcinogenic Agents; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D014028:Tobacco Smoke Pollution; D009288:Naproxen; D001241:Aspirin