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

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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.

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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-1β :

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

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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.

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Authors and Affiliations

  1. Center for the Study of Cancer Treatment Toxicities, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Rua Cel Nunes de Melo, 1127, Rodolfo Teófilo, 60430-270, Fortaleza, Ceará, Brazil

    Ronaldo A. Ribeiro, Carlos W. S. Wanderley, Deysi V. T. Wong, Caio A. V. G. Leite & Roberto C. P. Lima-Júnior

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

    Deysi V. T. Wong

  3. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    José Maurício S. C. Mota & Fernando Q. Cunha

  4. Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil

    Marcellus H. L. P. Souza

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  1. Ronaldo A. Ribeiro
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  2. Carlos W. S. Wanderley
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  4. José Maurício S. C. Mota
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  8. Roberto C. P. Lima-Júnior
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Correspondence to Carlos W. S. Wanderley or Roberto C. P. Lima-Júnior.

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Ribeiro, R.A., Wanderley, C.W.S., Wong, D.V.T. et al. Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives. Cancer Chemother Pharmacol 78, 881–893 (2016). https://doi.org/10.1007/s00280-016-3139-y

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