title: A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice.
abstract: OBJECTIVE
  Intestinal mucositis (IM) is a common side effect of anticancer agents. Despite polychemotherapy use in clinical practice, the pathogenesis of IM has been investigated in single drug injection animal models. However, the progression of IM could vary according to drug regimens. Thus, we aimed to develop a new experimental mucositis model induced by combining irinotecan and 5-fluorouracil (5-FU) treatments.
  
  
  METHODS
  IM was induced in male C57BL/6 mice by the intraperitoneal administration of either 0.9 % saline (5 mL/kg), irinotecan (IRI, 30 or 45 mg/kg), 5-FU (25, 37.5, or 50 mg/kg), or the combination of these doses (IRI + 5-FU) for 4 days. Animal survival, body mass variation, and diarrhea scores were evaluated daily. On the 7th day, the mice were euthanized, and intestinal samples were collected for histopathology and morphometric analysis, as well as for the determination of myeloperoxidase activity and cytokine dosage (TNF-α and IL-6).
  
  
  RESULTS
  The optimal dose combination that induced IM and presented no substantial mortality on the 7th day was IRI (45 mg/kg) + 5-FU (37.5 mg/kg), which was used for subsequent studies. IRI and 5-FU in combination induced significant diarrhea, body weight loss, intestinal damage, inflammatory cell infiltration, and increased levels of cytokines when compared with other groups (P < 0.05). Neither IRI nor 5-FU alone induced IM.
  
  
  CONCLUSIONS
  We developed a new experimental model of IM induced by combining irinotecan and 5-FU treatments, which will allow us to gain a better knowledge concerning the pathogenesis of this disease through the pharmacological modulation of key inflammatory mediators.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, Ceará, 60430-270, Brazil.
authors.forename: Venúcia B M
authors.initials: VB
authors.lastname: Pereira
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, Ceará, 60430-270, Brazil.
authors.forename: Anielle T
authors.initials: AT
authors.lastname: Melo
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, Ceará, 60430-270, Brazil.
authors.forename: Eudmar M
authors.initials: EM
authors.lastname: Assis-Júnior
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, Ceará, 60430-270, Brazil.
authors.forename: Deysi V T
authors.initials: DV
authors.lastname: Wong
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Gerly A C
authors.initials: GA
authors.lastname: Brito
authors.affiliation: Department of Pathology and Forensic Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Paulo R C
authors.initials: PR
authors.lastname: Almeida
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, Ceará, 60430-270, Brazil.
authors.forename: Ronaldo A
authors.initials: RA
authors.lastname: Ribeiro
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Rua Cel Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, Ceará, 60430-270, Brazil. robertocesarpljr@gmail.com.
authors.forename: Roberto C P
authors.initials: RC
authors.lastname: Lima-Júnior
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003967:Diarrhea; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D052016:Mucositis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009195:Peroxidase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000077146:Irinotecan; D009195:Peroxidase; D005472:Fluorouracil; D002166:Camptothecin
keywords: 5-Fluorouracil; Inflammation; Intestine; Irinotecan; Mucositis