title: Selective inhibition by aspirin and naproxen of mainstream cigarette smoke-induced genotoxicity and lung tumors in female mice.
abstract: The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in smoke-related lung carcinogenesis is still controversial. We have developed and validated a murine model for evaluating the tumorigenicity of mainstream cigarette smoke (MCS) and its modulation by chemopreventive agents. In the present study, the protective effects of the nonselective cyclooxygenase inhibitors aspirin and naproxen were investigated by using a total of 277 Swiss H neonatal mice of both genders. Groups of mice were exposed whole-body to MCS during the first 4 months of life, followed by an additional 3.5 months in filtered air in order to allow a better growth of tumors. Aspirin (1600 mg/kg diet) and naproxen (320 mg/kg diet) were given after weanling until the end of the experiment. After 4 months of exposure, MCS significantly enhanced the frequency of micronucleated normochromatic erythrocytes in the peripheral blood of mice, and naproxen prevented such systemic genotoxic damage in female mice. After 7.5 months, exposure of mice to MCS resulted in the formation of lung tumors, both benign and malignant, and in several other histopathological lesions detectable both in the respiratory tract and in the urinary tract. Aspirin and, even more sharply, naproxen significantly inhibited the formation of lung tumors in MCS-exposed mice, but this protective effect selectively occurred in female mice only. These results lend support to the views that estrogens are involved in smoke-related pulmonary carcinogenesis and that NSAIDs have antiestrogenic properties. The two NSAIDs proved to be safe and efficacious in the experimental model used.
authors.affiliation: National Center of Oncology, Sofia, 1756, Bulgaria.
authors.forename: Roumen
authors.initials: R
authors.lastname: Balansky
authors.affiliation: National Center of Oncology, Sofia, 1756, Bulgaria.
authors.forename: Gancho
authors.initials: G
authors.lastname: Ganchev
authors.affiliation: National Center of Oncology, Sofia, 1756, Bulgaria.
authors.forename: Marietta
authors.initials: M
authors.lastname: Iltcheva
authors.affiliation: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132, Genoa, Italy.
authors.forename: Rosanna T
authors.initials: RT
authors.lastname: Micale
authors.affiliation: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132, Genoa, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: La Maestra
authors.affiliation: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: D'Oria
authors.affiliation: Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, 20892, USA.
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.affiliation: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132, Genoa, Italy. sdf@unige.it.
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009288:Naproxen / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D016588:Anticarcinogenic Agents; D016861:Cyclooxygenase Inhibitors; D020847:Estrogen Receptor Modulators; D009288:Naproxen; D001241:Aspirin
keywords: Aspirin; Chemoprevention; Cigarette smoke; Lung tumors; Naproxen