The new selective GLP-2 receptor agonist, Elsiglutide, improves irinotecan-induced diarrhoea and mucositis in the rat. — ASN Events
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The new selective GLP-2 receptor agonist, Elsiglutide, improves irinotecan-induced diarrhoea and mucositis in the rat. (#224)

Bronwen Mayo 1 2 , Emma Bateman 1 , Andrea Stringer 2 , Erin Plews 1 , Anthony Wignall 1 , Belinda Wozniak 1 , Imogen White 3 , Claudio Pietra 4 , Sergio Cantoreggi 4 , Dorothy Keefe 1 2 5 6
  1. School of Medicine, University of Adelaide, Adelaide, SA, Australia
  2. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
  3. School of Medical Science, University of Adelaide, Adelaide, SA, Australia
  4. Research and Development, Helsinn Healthcare, Lugano, Switzerland
  5. Cancer Centre, Royal Adelaide Hospital, Adelaide, SA, Australia
  6. Centre for Clinical Research Excellence (CCRE) in Oral Health, University of Adelaide, Adelaide, SA, Australia

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 0.9mg/kg/day (subcutaneous, 5 days) was more effective than 1.8mg/kg (subcutaneous, 5 days) of elsiglutide, suggesting a bell-shape dose response.

Objectives:

To test whether a decreased dose of 0.45mg/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 200mg/kg at 0 hours intraperitoneal irinotecan, and daily subcutaneous dosing of 0.45mg/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±0.12g at 72hrs, 7.64±0.33g at 120hrs) compared with irinotecan alone (3.21±0.07g at 72hrs, 6.39±0.39g at 120hrs). 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 72hrs 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 0.45mg/kg/day following irinotecan administration may protect against and reduce damage to the small intestine. However, this data suggests the overall effect of 0.45mg/kg/day may be lower than that in previous experiments using 0.9mg/kg/day, but is still significant. Additional studies are required to explain the variations and to explore a range of effective doses. 

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