title: Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil.
abstract: BACKGROUND
  The use of the anticancer chemotherapeutic agent 5-fluorouracil (5-FU) is often limited by nausea, vomiting, constipation, and diarrhea; these side-effects persist long after treatment. The effects of 5-FU on enteric neurons have not been studied and may provide insight into the mechanisms underlying 5-FU-induced gastrointestinal dysfunction.
  
  
  METHODS
  Balb/c mice received intraperitoneal injections of 5-FU (23 mg/kg) 3 times/week for 14 days. Gastrointestinal transit was analysed in vivo prior to and following 3, 7, and 14 days of 5-FU treatment via serial x-ray imaging. Following 14 days of 5-FU administration, colons were collected for assessment of ex vivo colonic motility, gross morphological structure, and immunohistochemical analysis of myenteric neurons. Fecal lipocalin-2 and CD45+leukocytes in the colon were analysed as markers of intestinal inflammation.
  
  
  RESULTS
  Short-term administration of 5-FU (3 days) increased gastrointestinal transit, induced acute intestinal inflammation and reduced the proportion of neuronal nitric oxide synthase-immunoreactive neurons. Long-term treatment (7, 14 days) resulted in delayed gastrointestinal transit, inhibition of colonic migrating motor complexes, increased short and fragmented contractions, myenteric neuronal loss and a reduction in the number of ChAT-immunoreactive neurons after the inflammation was resolved. Gross morphological damage to the colon was observed following both short- and long-term 5-FU treatment.
  
  
  CONCLUSIONS
  Our results indicate that 5-FU induces accelerated gastrointestinal transit associated with acute intestinal inflammation at day 3 after the start of treatment, which may have led to persistent changes in the ENS observed after days 7 and 14 of treatment contributing to delayed gastrointestinal transit and colonic dysmotility.
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.|Western Centre for Health, Research and Education, Sunshine Hospital, St Albans, VIC, Australia.
authors.forename: R M
authors.initials: RM
authors.lastname: McQuade
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.|Western Centre for Health, Research and Education, Sunshine Hospital, St Albans, VIC, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Stojanovska
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.|Western Centre for Health, Research and Education, Sunshine Hospital, St Albans, VIC, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Donald
authors.affiliation: Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica (IQM) y al Instituto de Investigación en Ciencias de la Alimentación (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Abalo
authors.affiliation: Department of Physiology, Melbourne University, Melbourne, VIC, Australia.
authors.forename: J C
authors.initials: JC
authors.lastname: Bornstein
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.|Western Centre for Health, Research and Education, Sunshine Hospital, St Albans, VIC, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Nurgali
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D003106:Colon / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D017615:Enteric Nervous System / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology*; D005472:Fluorouracil / Q000633:toxicity*; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000503:physiopathology*; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques
chemical_list: D000970:Antineoplastic Agents; D005472:Fluorouracil
keywords: 5-FU; 5-fluorouracil; colonic motility; enteric neuropathy; gastrointestinal transit; myenteric neurons