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

Abstract

Key Points• 5-FU is the first-line chemotherapy for colorectal cancer; its use is associated with severe long-term gastrointestinal side-effects. Mechanisms underlying 5-FU-induced gastrointestinal dysfunction have not been investigated in depth.• 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.• These findings provide insight into the mechanisms underlying chemotherapy-induced gastrointestinal dysfunction. AbstractBackground 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 synthaseimmunoreactive 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 longterm 5-FU treatment. Conclusions & Inferences Our

Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments

“…However, the effects of chemotherapeutics on ENS and GI dysfunction have been largely overlooked until recently. A study investigating the effects of 5-fluorouracil-induced dysmotility in mice uncovered myenteric neuronal loss alongside delayed GI transit and inhibition of propagating colonic contractions (McQuade et al, 2016). Similar results have been demonstrated following oxaliplatin administration in mice, and cisplatin administration in rats, where enteric neuronal loss was associated with a reduction in colonic motor activity and reduced GI transit time, respectively (Vera et al, 2011; Wafai et al, 2013).…”

Irinotecan-Induced Gastrointestinal Dysfunction Is Associated with Enteric Neuropathy, but Increased Numbers of Cholinergic Myenteric Neurons

“…Gastrointestinal transit was studied by X-ray prior to first treatment (day 0) and at 3, 7, and 14 days and 7 days post-treatment of IRI treatment ( n = 5 mice/group) as described previously (McQuade R. et al, 2016; McQuade R. M. et al, 2016). Briefly, the contrast agent, 0.4 mL of suspended barium sulfate (X-OPAQUE-HD, 2.5 g/mL), was administered via oral gavage.…”

“…Contractions that propagated less than 50% of the colonic length were considered to be short contractions (SCs). Incomplete contractions occurring synchronously at different parts of the colon rather than propagating over the length of the colon were defined as fragmented contractions (FCs) (McQuade R. et al, 2016). …”

“…Paraffin embedded colon sections were cut 5 μm thick and deparaffinized, cleared, and rehydrated in graded ethanol concentrations.). To examine the morphological changes to the colon, standard Haematoxylin, and Eosin (H&E) staining protocol was followed (McQuade R. et al, 2016). Ten randomly selected sections per preparation were analyzed and scored on the following parameters: changes in crypt architecture (0–5), reduction in crypt length (0–5), mucosal ulceration (0–5), and immune cell infiltration (0–5) (total score 20) (Rahman et al, 2016).…”

Resveratrol alleviates oxidative damage in enteric neurons and associated gastrointestinal dysfunction caused by chemotherapeutic agent oxaliplatin

“…Sample size was calculated based on our previous studies on enteric neuropathy and intestinal dysmotility associated with chemotherapy [8,38].To detect a 30% change at a power 0.8 and α = 0.05 with 10% SD, the effect size should be minimum n=5 animals per group as calculated by the GPOWER program. Data were assessed using one way ANOVA and Tukey's post-hoc test.…”