Abstract
Gastrointestinal dysfunction is a common side-effect of chemotherapy leading to dose reductions and treatment delays. These side-effects may persist up to 10 years post-treatment. A topoisomerase I inhibitor, irinotecan (IRI), commonly used for the treatment of colorectal cancer, is associated with severe acute and delayed-onset diarrhea. The long-term effects of IRI may be due to damage to enteric neurons innervating the gastrointestinal tract and controlling its functions. Balb/c mice received intraperitoneal injections of IRI (30 mg/kg−1) 3 times a week for 14 days, sham-treated mice received sterile water (vehicle) injections. In vivo analysis of gastrointestinal transit via serial x-ray imaging, facal water content, assessment of gross morphological damage and immunohistochemical analysis of myenteric neurons were performed at 3, 7 and 14 days following the first injection and at 7 days post-treatment. Ex vivo colonic motility was analyzed at 14 days following the first injection and 7 days post-treatment. Mucosal damage and inflammation were found following both short and long-term treatment with IRI. IRI-induced neuronal loss and increases in the number and proportion of ChAT-IR neurons and the density of VAChT-IR fibers were associated with changes in colonic motility, gastrointestinal transit and fecal water content. These changes persisted in post-treatment mice. Taken together this work has demonstrated for the first time that IRI-induced inflammation, neuronal loss and altered cholinergic expression is associated with the development of IRI-induced long-term gastrointestinal dysfunction and diarrhea.
Highlights
A combination of irinotecan (IRI) with 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFIRI) is a common and effective therapy administered to colorectal cancer (CRC) patients (Conti et al, 1996; Saltz et al, 2000)
No differences in transit time to the caecum or colon were found at days 7, 14 or post-treatment when compared to day 0 (Figure 2A, Table 1)
Tracing barium movement allowed for the analysis of real time transit speed, gastrointestinal organ filling and emptying does not happen simultaneously, we further analyzed the time taken for complete barium emptying from specific gastrointestinal regions
Summary
A combination of irinotecan (IRI) with 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFIRI) is a common and effective therapy administered to CRC patients (Conti et al, 1996; Saltz et al, 2000). Clinical trials in patients with metastatic CRC have demonstrated a significant survival advantage for FOLFIRI compared with 5-FU/LV alone (Douillard et al, 2000; Saltz et al, 2000), but major dose-limiting toxicities such as neutropenia and chronic diarrhea diminish the clinical efficacy of FOLFIRI treatment (Armand, 1996; Rothenberg et al, 1996; Weekes et al, 2009). IRI-induced diarrhea is typically severe, resulting in hospitalisations, dosereductions and delays, and termination of treatment in many cases (Swami et al, 2013). Though the prevalence and severity of IRI-induced diarrhea vary greatly depending on regime specifics such as dosage and adjuvant therapies, rates as high as 80% have been reported (Rothenberg et al, 1996)
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