title: Assay of lapatinib in murine models of cigarette smoke carcinogenesis.
abstract: Lapatinib, a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), is prescribed for the treatment of patients with metastatic breast cancer overexpressing HER-2. Involvement of this drug in pulmonary carcinogenesis has been poorly investigated. We used murine models suitable to evaluate cigarette smoke-related molecular and histopathological alterations. A total of 481 Swiss H mice were used. The mice were exposed to mainstream cigarette smoke (MCS) during the first four months of life. After 10 weeks, MCS caused an elevation of bulky DNA adducts, oxidative DNA damage and an extensive downregulation of microRNAs in lung. After four months, an increase in micronucleus frequency was observed in peripheral blood erythrocytes. After 7.5 months, histopathological alterations were detected in the lung, also including benign tumors and malignant tumors, and in the urinary tract. A subchronic toxicity study assessed the non-toxic doses of lapatinib, administered daily with the diet after weaning. After 10 weeks, lapatinib significantly attenuated the MCS-related nucleotide changes and upregulated several low-intensity microRNAs in lung. The drug poorly affected the MCS systemic genotoxicity and had modest protective effects on MCS-induced preneoplastic lesions in lung and kidney, when administered under conditions that temporarily mimicked interventions either in current smokers or ex-smokers. On the other hand, it caused some toxicity to the liver. Thus, on the whole, lapatinib appears to have a low impact in the smoke-related lung carcinogenesis models used, especially in terms of tumorigenic response.
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy, National Center of Oncology, Sofia-1756, Bulgaria.
authors: Roumen
authors: R
authors: Balansky
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy, IRCCS AOU San Martino - IST, 16132 Genoa, Italy and.
authors: Alberto
authors: A
authors: Izzotti
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy.
authors: Francesco
authors: F
authors: D'Agostini
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy.
authors: Mariagrazia
authors: M
authors: Longobardi
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy.
authors: Rosanna T
authors: RT
authors: Micale
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy.
authors: Sebastiano
authors: S
authors: La Maestra
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy.
authors: Anna
authors: A
authors: Camoirano
authors: National Center of Oncology, Sofia-1756, Bulgaria.
authors: Gancho
authors: G
authors: Ganchev
authors: National Center of Oncology, Sofia-1756, Bulgaria.
authors: Marietta
authors: M
authors: Iltcheva
authors: Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20892, USA.
authors: Vernon E
authors: VE
authors: Steele
authors: Department of Health Sciences, University of Genoa, Via A. Pastore 1, 16132 Genoa, Italy, sdf@unige.it.
authors: Silvio
authors: S
authors: De Flora
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D018736:DNA Adducts; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000077341:Lapatinib; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D059550:Toxicity Tests, Subchronic
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014028:Tobacco Smoke Pollution; D000077341:Lapatinib