A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice

• Published in: Cancer chemotherapy and pharmacology 2016-02, Vol.77 (2), p.323-332
• Main Authors: Pereira, Venúcia B. M., Melo, Anielle T., Assis-Júnior, Eudmar M., Wong, Deysi V. T., Brito, Gerly A. C., Almeida, Paulo R. C., Ribeiro, Ronaldo A., Lima-Júnior, Roberto C. P.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Cancer Research; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil - administration & dosage; Fluorouracil - pharmacokinetics; Interleukin-6 - metabolism; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Models, Animal; Mucositis - chemically induced; Mucositis - metabolism; Mucositis - physiopathology; Oncology; Original Article; Peroxidase - metabolism; Pharmacology/Toxicology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2938-x

Purpose 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