Chemotherapy-associated steatohepatitis induced by irinotecan: a novel animal model

Purpose Nonalcoholic steatohepatitis (NASH) has been associated with irinotecan (IRI)-based cancer chemotherapy regimens. The purpose of this study was to propose and test a consistent model of IRI-induced NASH, filling a gap in the medical literature. Methods Swiss male mice were distributed in gro...

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Published in:	Cancer chemotherapy and pharmacology Vol. 74; no. 4; pp. 711 - 720
Main Authors:	Costa, Marcelo Leite Vieira, Lima-Júnior, Roberto César Pereira, Aragão, Karoline Sabóia, Medeiros, Raul Pinheiro, Marques-Neto, Raphael Dias, de Sá Grassi, Lucas, Leite, Leandro Linhares, Nunes, Lorena Guimaraes, de Mesquita Neto, José Wilson Benevides, de Castro Brito, Gerly Anne, de Souza, Marcellus Henrique Loiola Pontes, de Almeida, Paulo Roberto Carvalho, Ribeiro, Ronaldo Albuquerque
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2014 Springer Springer Nature B.V
Subjects:	Alanine Transaminase - blood Animals Antineoplastic agents Antineoplastic Agents, Phytogenic - metabolism Aspartate Aminotransferases - blood Biological and medical sciences Camptothecin - analogs & derivatives Camptothecin - metabolism Camptothecin - pharmacology Cancer Research Disease Models, Animal Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Fatty Liver - chemically induced Fatty Liver - metabolism Fatty Liver - pathology Fatty Liver - physiopathology Humans Interleukin-1beta - metabolism Liver - metabolism Liver - pathology Male Medical sciences Medicine Medicine & Public Health Mice Oncology Original Article Peroxidase - metabolism Pharmacology. Drug treatments Pharmacology/Toxicology Time Factors Tumor Necrosis Factor-alpha - metabolism Weight Loss - drug effects Irinotecan Animal model Toxicity Steatohepatitis Liver Camptothecin derivatives Antineoplastic agent Digestive system Enzyme DNA topoisomerase Enzyme inhibitor Steatosis Chemotherapy Isomerases Treatment Topoisomerase I inhibitor
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Summary:	Purpose Nonalcoholic steatohepatitis (NASH) has been associated with irinotecan (IRI)-based cancer chemotherapy regimens. The purpose of this study was to propose and test a consistent model of IRI-induced NASH, filling a gap in the medical literature. Methods Swiss male mice were distributed in groups ( n = 8) and injected with saline (5 mL/kg, i.p.; control) or IRI (25, 50, 75 or 100 mg/kg, i.p.) thrice a week for 7 weeks. Blood samples were collected to measure the serum concentrations of proteins, alanine and aspartate aminotransferases (ALT and AST). Each week animals were euthanized, and the livers were submitted to myeloperoxidase (MPO) assay, lipid dosage, immunohistochemistry for inducible nitric oxide synthase (iNOS), TNF-α and interleukin-1β (IL-1β), and histopathological analysis. Survival rates were also determined. Results Mice treated with IRI had a significantly ( p < 0.05) lower survival rate than controls and time- and dose-dependent body weight loss. ALT and AST plasma levels increased in relation to controls only in mice receiving IRI 50 mg/kg ( p < 0.05). The histopathological features characteristic of NASH was observed, including steatosis, lobular neutrophil infiltration and ballooning hepatocytic degeneration. Additional findings included increased MPO, lipid accumulation, portal neutrophil infiltration, IL-1β and iNOS expression and fibrosis in liver tissues and low serum protein levels compared to controls. Conclusion This is the first report of a consistent model of IRI-induced NASH capable of mimicking clinical findings.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0344-5704 1432-0843
DOI:	10.1007/s00280-014-2434-8