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A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice

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Abstract

Purpose

Intestinal mucositis (IM) is a common side effect of anticancer agents. Despite polychemotherapy use in clinical practice, the pathogenesis of IM has been investigated in single drug injection animal models. However, the progression of IM could vary according to drug regimens. Thus, we aimed to develop a new experimental mucositis model induced by combining irinotecan and 5-fluorouracil (5-FU) treatments.

Methods

IM was induced in male C57BL/6 mice by the intraperitoneal administration of either 0.9 % saline (5 mL/kg), irinotecan (IRI, 30 or 45 mg/kg), 5-FU (25, 37.5, or 50 mg/kg), or the combination of these doses (IRI + 5-FU) for 4 days. Animal survival, body mass variation, and diarrhea scores were evaluated daily. On the 7th day, the mice were euthanized, and intestinal samples were collected for histopathology and morphometric analysis, as well as for the determination of myeloperoxidase activity and cytokine dosage (TNF-α and IL-6).

Results

The optimal dose combination that induced IM and presented no substantial mortality on the 7th day was IRI (45 mg/kg) + 5-FU (37.5 mg/kg), which was used for subsequent studies. IRI and 5-FU in combination induced significant diarrhea, body weight loss, intestinal damage, inflammatory cell infiltration, and increased levels of cytokines when compared with other groups (P < 0.05). Neither IRI nor 5-FU alone induced IM.

Conclusions

We developed a new experimental model of IM induced by combining irinotecan and 5-FU treatments, which will allow us to gain a better knowledge concerning the pathogenesis of this disease through the pharmacological modulation of key inflammatory mediators.

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Acknowledgments

We are grateful to Maria Silvandira Freire for her technical assistance. This study was supported by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant Nos 308879/2009-0, 307143/2014-7) and FUNCAP (Fundação Cearense de Apoio ao Desenvolvimento Científico, Grant No. 11.01.00/08). G.A.C.B., R.A.R., and R.C.P.L.J. are CNPq fellowship holders.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, Ceará, 60430-270, Brazil

    Venúcia B. M. Pereira, Anielle T. Melo, Eudmar M. Assis-Júnior, Deysi V. T. Wong, Ronaldo A. Ribeiro & Roberto C. P. Lima-Júnior

  2. Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil

    Gerly A. C. Brito

  3. Department of Pathology and Forensic Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil

    Paulo R. C. Almeida

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  1. Venúcia B. M. Pereira
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Correspondence to Roberto C. P. Lima-Júnior.

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Pereira, V.B.M., Melo, A.T., Assis-Júnior, E.M. et al. A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice. Cancer Chemother Pharmacol 77, 323–332 (2016). https://doi.org/10.1007/s00280-015-2938-x

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