title: Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives.
abstract: OBJECTIVE
  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.
authors: 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.
authors: Ronaldo A
authors: RA
authors: Ribeiro
authors: 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. cwswanderley@gmail.com.
authors: Carlos W S
authors: CW
authors: Wanderley
authors: 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.|Department of Pathology and Forensic Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
authors: Deysi V T
authors: DV
authors: Wong
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors: José Maurício S C
authors: JM
authors: Mota
authors: 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.
authors: Caio A V G
authors: CA
authors: Leite
authors: Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
authors: Marcellus H L P
authors: MH
authors: Souza
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors: Fernando Q
authors: FQ
authors: Cunha
authors: 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. robertocesarpljr@gmail.com.
authors: Roberto C P
authors: RC
authors: Lima-Júnior
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D016207:Cytokines / Q000378:metabolism; D005472:Fluorouracil / Q000009:adverse effects*; D006801:Humans; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000077146:Irinotecan; D052016:Mucositis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D018121:Receptors, Cytokine / Q000187:drug effects / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D018121:Receptors, Cytokine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin
keywords: Cancer chemotherapy; Cytokines; Inflammation; Intestine; Irinotecan; Mucositis; Toll-like receptors