Irinotecan induces intestinal atrophy and compromises duodenal motility and mucosal permeability: in vivo and in vitro evaluations
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Purpose
Intestinal toxicity is a significant adverse effect of chemotherapy, with no effective treatments currently available. This study aimed to evaluate the effects of irinotecan (IRT) on; (i) duodenal motility and mucosal barrier function, (ii) histopathological changes along the small intestine and colon, and (iii) faecal water content, to better understand IRT-induced intestinal toxicity, and to support future treatment strategies to minimize these effects.
Methods
Sprague Dawley rats were anaesthetized with thiobarbiturate, and a 30-mm long segment of the proximal duodenum with an intact blood supply was perfused in situ . The effects of IRT on duodenal motility and blood-to-lumen clearance of 3 H-mannitol were investigated. In separate experiments, intestinal toxicity was induced in rats by intravenous (i.v.) dosing with IRT. After 72 h post IRT administration, the rats were sacrificed and the small intestine and the colon were excised for histological analysis. Fecal water contents and change in body weight were also measured. In addition, effects of IRT on cell viability were evaluated via Caco-2 cell culture, IRT treatment, and resazurin reduction assays.
Result
Intravenous dosing of IRT (60 mg/kg) significantly induced robust and sustained increase in both duodenal motility (+277%) and in mucosal paracellular permeability (+85%). Moreover, IRT in doses of 180 mg/kg and 200 mg/kg (i.p.), induced similar reduction in villus length evaluated 72 h post administration; in duodenum (-52% and -45%, respectively) and jejunum (-37% and -33%), but was without effects in ileum. IRT induced increases in jejunal crypt depth (+48% and +41%), but did not significantly influence the crypt depth in duodenum, ileum or colon. IRT induced increases in fecal water content by +19% and +16%, respectively, and caused significant body weight reductions by 10% and 13%, respectively. IRT exposing of Caco-2 cells resulted in a significant decrease in viability, and a resulting IC 50 value of 1289 μM.
Conclusions
Our novel results show that IRT highly increases duodenal motility and impair mucosal barrier function. In addition, IRT induces diarrhoea, and demonstrates histopathological in the proximal small intestine. These findings contribute to the basic physiological understanding, and provide potentially new innovations for treatment of IRT-induced intestinal toxicity.
