Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives
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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.
A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion.
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.
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.
KeywordsCancer chemotherapy Irinotecan Inflammation Intestine Mucositis Cytokines Toll-like receptors
Inflammasome adaptor protein apoptosis-associated speck-like protein containing CARD
Chemokine (C–C motif) Ligand
Chemokine (C–X–C motif) ligand
Chemokine (C–X–C Motif) receptor
Damage-associated molecular pattern
Irinotecan with fluorouracil and folinic acid
Interleukin-1 receptor antagonist
Inducible nitric oxide synthase
Irinotecan and oxaliplatin
Myeloid differentiation primary response gene 88
Dihydronicotinamide adenine dinucleotide phosphate
Nuclear factor kappa B
Pathogen-associated molecular pattern
Reactive oxygen species
7-Ethyl-10-hydroxycamptothecin or the active metabolite of irinotecan
SN-38 glucuronide form
Toll/IL-1 receptor domain
Tumor necrosis factor-α
UDP glucuronosyltransferase 1 family, polypeptide A1
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).
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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