Apoptosis, proliferation and inflammation are improved after treatment with the new selective GLP-2 receptor agonist, Elsiglutide, in a rat model of irinotecan-induced mucositis. — ASN Events
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Apoptosis, proliferation and inflammation are improved after treatment with the new selective GLP-2 receptor agonist, Elsiglutide, in a rat model of irinotecan-induced mucositis. (#225)

Bronwen Mayo 1 2 , Andrea Stringer 2 , Emma Bateman 1 , Joanne Bowen 3 , 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:

Gastrointestinal mucositis (GIM) is a severe and debilitating side-effect of cancer therapy. There are currently few treatments which effectively prevent or ameliorate GIM. In a previous study it was shown that elsiglutide, a selective glucagon-like peptide-2 (GLP-2) receptor agonist, improved diarrhoea and histological damage associated with irinotecan-induced GIM in a rat model. Increased apoptosis, inflammation and decreased proliferation are associated with irinotecan-induced GIM. It is thought that elsiglutide may improve diarrhoea and damage through altering these gastrointestinal cellular effects.

Objectives:

To determine if elsiglutide reduces apoptosis and inflammation, and increases proliferation in the small intestinal crypts of the rat, following irinotecan administration.

Method:

Dark Agouti rats were given irinotecan once (200mg/kg, 0 hrs) and elsiglutide (0.9mg/kg or 1.8mg/kg per day, subcutaneous) for 5 days, and killed at 6, 72 or 120 hrs (n=6). Markers for apoptosis (Caspase-3), proliferation (Ki67) and inflammation (myeloperoxidase, MPO) were analysed using immunohistochemistry in the jejunum and ileum. Positive stained cells were counted per crypt or field of view (FOV).

Results:

Apoptosis was significantly (p<0.05, cells/crypt) reduced following 0.9mg/kg/day elsiglutide and irinotecan at 6hrs (Jejunum 10.15±1.00; Ileum 13.85±1.44) compared with irinotecan control (Jejunum 14.84±1.15; Ileum 22.49±1.08). Proliferation was significantly (p<0.05, cells/demi-crypt) increased at 72hrs (peak damage) in this group (Jejunum 31.45±2.78; Ileum 28.47±2.64) compared with irinotecan alone (Jejunum 18.98±2.13; Ileum 18.64±1.62). Staining also showed that 0.9mg/kg/day elsiglutide given after irinotecan significantly (p<0.01, cells/FOV) reduces the number of MPO positive inflammatory cells in the jejunum (72hrs 67.02±6.72; 120hrs 42.08±5.52) compared with irinotecan alone (72hrs 106.69±6.04; 120hrs 64.30±7.65).

Conclusions: 

Elsiglutide (0.9mg/kg/day) decreases apoptosis and inflammation, which may be contributors to irinotecan-induced GIM. In addition, elsiglutide improves proliferation of crypt cells, which may shorten the duration of GIM. These results provide a basis for future studies with elsiglutide to determine the exact mechanisms for this phenomenon.

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