Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 4, pp 931–942

Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation

  • Roberto César P. Lima-Júnior
  • Aline A. Figueiredo
  • Helano C. Freitas
  • Maria Luisa P. Melo
  • Deysi Viviana T. Wong
  • Caio Abner V. G. Leite
  • Raul P. Medeiros
  • Raphael D. Marques-Neto
  • Mariana L. Vale
  • Gerly Anne C. Brito
  • Reinaldo B. Oriá
  • Marcellus H. L. P. Souza
  • Fernando Q. Cunha
  • Ronaldo A. Ribeiro
Original Article

Abstract

Purpose

Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis.

Methods

iNOS-knockout (iNOS−/−) and C57BL/6 (WT, wild type) animals (n = 5–6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility.

Results

Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS−/− mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS−/− mice when compared with wild-type animals that were given irinotecan.

Conclusions

This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction.

Keywords

Irinotecan Intestinal mucositis Nitric oxide Cytokines 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Roberto César P. Lima-Júnior
    • 1
  • Aline A. Figueiredo
    • 1
  • Helano C. Freitas
    • 1
  • Maria Luisa P. Melo
    • 1
  • Deysi Viviana T. Wong
    • 1
  • Caio Abner V. G. Leite
    • 1
  • Raul P. Medeiros
    • 1
  • Raphael D. Marques-Neto
    • 1
  • Mariana L. Vale
    • 1
  • Gerly Anne C. Brito
    • 2
  • Reinaldo B. Oriá
    • 2
  • Marcellus H. L. P. Souza
    • 1
  • Fernando Q. Cunha
    • 3
  • Ronaldo A. Ribeiro
    • 1
    • 4
  1. 1.Department of Physiology and Pharmacology, Faculty of MedicineFederal University of CearáFortalezaBrazil
  2. 2.Department of Morphology, Faculty of MedicineFederal University of CearáCearáBrazil
  3. 3.Department of PharmacologySchool of Medicine of Ribeirão Preto, University of São PauloSão PauloBrazil
  4. 4.Department of Clinical OncologyCancer Institute of CearáFortalezaBrazil

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