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

• Published in: Neurogastroenterology and motility Vol. 28; no. 12; pp. 1861 - 1875
• Main Authors: McQuade, R. M., Stojanovska, V., Donald, E., Abalo, R., Bornstein, J. C., Nurgali, K.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.12.2016
• Subjects: 5‐fluorouracil; 5‐FU; Animals; Antineoplastic Agents - toxicity; Cancer; Colon; Colon - diagnostic imaging; Colon - drug effects; Colon - physiopathology; colonic motility; Enteric Nervous System - diagnostic imaging; Enteric Nervous System - drug effects; Enteric Nervous System - physiopathology; enteric neuropathy; Fluorouracil - toxicity; Gastrointestinal Diseases - chemically induced; Gastrointestinal Diseases - diagnostic imaging; Gastrointestinal Diseases - physiopathology; gastrointestinal transit; Gastrointestinal Transit - drug effects; Gastrointestinal Transit - physiology; Inflammation; Male; Mice; Mice, Inbred BALB C; Morphology; myenteric neurons; Organ Culture Techniques; Rodents; 5-fluorouracil; colonic motility; gastrointestinal transit; myenteric neurons; enteric neuropathy; 5-FU
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.12890

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.