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Cancer Chemotherapy and Pharmacology

, Volume 78, Issue 5, pp 881–893 | Cite as

Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives

  • Ronaldo A. Ribeiro
  • Carlos W. S. Wanderley
  • Deysi V. T. Wong
  • José Maurício S. C. Mota
  • Caio A. V. G. Leite
  • Marcellus H. L. P. Souza
  • Fernando Q. Cunha
  • Roberto C. P. Lima-Júnior
Review Article
Part of the following topical collections:
  1. Cytotoxic Reviews

Abstract

Purpose

Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis.

Methods

A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion.

Results

Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis.

Conclusions

IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.

Keywords

Cancer chemotherapy Irinotecan Inflammation Intestine Mucositis Cytokines Toll-like receptors 

Abbreviations

ASC

Inflammasome adaptor protein apoptosis-associated speck-like protein containing CARD

CCL

Chemokine (C–C motif) Ligand

CID

Chemotherapy-induced diarrhea

COX-2

Cyclooxygenase-2

CPT-11

Irinotecan

CXCL

Chemokine (C–X–C motif) ligand

CXCR

Chemokine (C–X–C Motif) receptor

DAMP

Damage-associated molecular pattern

DC

Dendritic cell

FOLFIRI

Irinotecan with fluorouracil and folinic acid

IL-18

Interleukin-18

IL-18R

Interleukin-18 receptor

IL-1R

Interleukin-1 receptor

IL-1RA

Interleukin-1 receptor antagonist

IL-

Interleukin-1β

IL-33

Interleukin-33

iNOS

Inducible nitric oxide synthase

IROX

Irinotecan and oxaliplatin

MyD88

Myeloid differentiation primary response gene 88

NADPH

Dihydronicotinamide adenine dinucleotide phosphate

NF-κB

Nuclear factor kappa B

NO

Nitric oxide

NOX-2

NADPH oxidase-2

PAMP

Pathogen-associated molecular pattern

ROS

Reactive oxygen species

5-FU

5-Fluorouracil

SN-38

7-Ethyl-10-hydroxycamptothecin or the active metabolite of irinotecan

SN-38G

SN-38 glucuronide form

ST2

Interleukin-33 receptor

TIR

Toll/IL-1 receptor domain

TLR

Toll-like receptor

TNF-α

Tumor necrosis factor-α

UGT1A1

UDP glucuronosyltransferase 1 family, polypeptide A1

Notes

Acknowledgments

This review is dedicated to the loving memory of Prof. Dr. Ronaldo Albuquerque Ribeiro (in memoriam). R. C. P. Lima-Júnior received a research Grant from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Grant Nos.: 307143/2014-7 and 458872/2014-8. This work was also supported by Grants from CAPES (Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Grant CAPES-PROEX 2862/2013) and FUNCAP (Fundação Cearense de Apoio ao Desenvolvimento Científico, Grant PRONEX PR2-0101-00054.01.00/15).

Author’s contribution

RA. Ribeiro, C.W.S. Wanderley, D.V.T. Wong, J.M.S.C. Mota, C.A.V.G. Leite, M.H.L.P. Souza, F.Q. Cunha, and R.C.P. Lima-Júnior all contributed to the literature searching and reviewing and to the writing of the manuscript. C.A.V.G. Leite and C.W.S. Wanderley constructed the illustration and table, respectively. C.W.S. Wanderley, D.V.T. Wong, J.M.S.C. Mota, C.A.V.G. Leite, M.H.L.P. Souza, F.Q. Cunha, and R.C.P. Lima-Júnior approved the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ronaldo A. Ribeiro
    • 1
  • Carlos W. S. Wanderley
    • 1
  • Deysi V. T. Wong
    • 1
    • 2
  • José Maurício S. C. Mota
    • 3
  • Caio A. V. G. Leite
    • 1
  • Marcellus H. L. P. Souza
    • 4
  • Fernando Q. Cunha
    • 3
  • Roberto C. P. Lima-Júnior
    • 1
  1. 1.Center for the Study of Cancer Treatment Toxicities, Department of Physiology and Pharmacology, Faculty of MedicineFederal University of CearáFortalezaBrazil
  2. 2.Department of Pathology and Forensic Medicine, Faculty of MedicineFederal University of CearáFortalezaBrazil
  3. 3.Department of Pharmacology, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  4. 4.Department of Clinical Medicine, Faculty of MedicineFederal University of CearáFortalezaBrazil

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