The new selective glp-2 receptor agonist, elsiglutide, improves irinotecan-induced diarrhoea and mucositis in the rat

Abstract

Introduction: Irinotecan is a common chemotherapeutic agent that's use is associated with severe gastrointestinal mucositis presenting as diarrhoea, nausea, vomiting, and pain and ulceration of the digestive tract. Elsiglutide, a glucagon-like peptide-2 receptor agonist, has recently been shown to decrease diarrhoea and gastrointestinal (GI) damage caused by irinotecan administration in a rat model. Interestingly, the trialled doses showed that 0.9 mg/kg/day (subcutaneous, 5 days) was more effective than 1.8 mg/kg (subcutaneous, 5 days) of elsiglutide, suggesting a bell-shape dose response. Objectives: To test whether a decreased dose of 0.45 mg/kg of elsiglutide further improves the GI toxicity associated with irinotecan in the rat model of irinotecan-induced mucositis. Method: Dark Agouti rat model of irinotecan-induced mucositis was used to characterise effects of lower dose elsiglutide on irinotecan-induced diarrhoea and GI damage. Animals received 200 mg/kg at 0 hours intraperitoneal irinotecan, and daily subcutaneous dosing of 0.45 mg/kg elsiglutide for 5 days, then were killed at 6, 72 or 120 hours post-chemotherapy (n = 6). Jejunum and ileum were taken for histology and microdissection. Results: Elsiglutide reduced duration of severe diarrhoea. Small intestinal wet weight increased significantly (grams, p < 0.05) following elsiglutide with irinotecan (3.75 +/- 0.12 g at 72 hrs, 7.64 +/- 0.33 g at 120 hrs) compared with irinotecan alone (3.21 +/- 0.07 g at 72 hrs, 6.39 +/- 0.39 g at 120 hrs). Villous blunting, crypt ablation and enterocyte disruption improved and inflammatory infiltrate decreased following elsiglutide and irinotecan compared with irinotecan alone. Villous area significantly increased (mm2, p < 0.05) at 72 hrs following elsiglutide with irinotecan (Jejunum 0.061 +/- 0.004; Ileum 0.042 +/- 0.003) when compared with irinotecan alone (Jejunum 0.042 +/- 0.005; Ileum 0.03 +/- 0.004). Conclusions: Elsiglutide 0.45 mg/kg/day following irinotecan administration may protect against and reduce damage to the small intestine. However, this data suggests the overall effect of 0.45 mg/kg/day may be lower than that in previous experiments using 0.9 mg/kg/day, but is still significant. Additional studies are required to explain the variations and to explore a range of effective doses.