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.

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.

5-Fluorouracil (5-FU) is the first-line chemotherapy for colorectal cancer; its use is associated with severe long-term gastrointestinal side-effects. This is the first study in a mouse model demonstrating that short-term 5-FU treatment induces increased gastrointestinal transit associated with acute intestinal inflammation, which may lead to persistent changes in the ENS contributing to delayed gastrointestinal transit and colonic dysmotility.

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