Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil

R. M. McQuade, V. Stojanovska, E. Donald, R. Abalo, J. C. Bornstein, K. Nurgali

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28 Citations (Scopus)

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. Key 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 & Inferences: 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.

Original languageEnglish
Pages (from-to)1861-1875
Number of pages15
JournalNeurogastroenterology & Motility
Volume28
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016
Externally publishedYes

Keywords

  • 5-fluorouracil
  • 5-FU
  • colonic motility
  • enteric neuropathy
  • gastrointestinal transit
  • myenteric neurons

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