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

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Abstract

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.

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Acknowledgments

We are grateful to Maria Silvandira Freire and Karina Felismino da Silva Santos for technical assistance. The authors received financial support from CNPq [National Council for Research and Development], CAPES [Brazilian government program for continuing higher education] and FUNCAP [Ceará State Foundation for Research Support]. RAR, MHLPS and GACB are CNPq scholarship holders.

Conflict of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará (UFC), Rua Cel. Nunes de Melo, 1127-Rodolfo Teófilo, 60430-270, Fortaleza, Ceará, Caixa-Postal: 3157, Brazil

    Marcelo Leite Vieira Costa, Roberto César Pereira Lima-Júnior, Karoline Sabóia Aragão, Raul Pinheiro Medeiros, Raphael Dias Marques-Neto, Lucas de Sá Grassi, Leandro Linhares Leite, Lorena Guimaraes Nunes, Marcellus Henrique Loiola Pontes de Souza & Ronaldo Albuquerque Ribeiro

  2. Department of Surgery, Ceará Cancer Institute (ICC), Fortaleza, Ceará, Brazil

    Marcelo Leite Vieira Costa & José Wilson Benevides de Mesquita Neto

  3. Department of Morphology, School of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil

    Gerly Anne de Castro Brito

  4. Department of Pathology, School of Medicine, Federal University of Ceará (UFC), Fortaleza, Ceará, Brazil

    Paulo Roberto Carvalho de Almeida

  5. Department of Clinical Oncology, Ceará Cancer Institute (ICC), Fortaleza, Ceará, Brazil

    Ronaldo Albuquerque Ribeiro

Authors
  1. Marcelo Leite Vieira Costa
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  2. Roberto César Pereira Lima-Júnior
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  3. Karoline Sabóia Aragão
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  6. Lucas de Sá Grassi
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  7. Leandro Linhares Leite
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  8. Lorena Guimaraes Nunes
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  9. José Wilson Benevides de Mesquita Neto
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  10. Gerly Anne de Castro Brito
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  11. Marcellus Henrique Loiola Pontes de Souza
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  12. Paulo Roberto Carvalho de Almeida
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  13. Ronaldo Albuquerque Ribeiro
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Corresponding author

Correspondence to Ronaldo Albuquerque Ribeiro.

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Costa, M.L.V., Lima-Júnior, R.C.P., Aragão, K.S. et al. Chemotherapy-associated steatohepatitis induced by irinotecan: a novel animal model. Cancer Chemother Pharmacol 74, 711–720 (2014). https://doi.org/10.1007/s00280-014-2434-8

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  • DOI: https://doi.org/10.1007/s00280-014-2434-8

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