Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage.
Glucagon-like peptide-2 and its dipeptidyl peptidase (DP-IV) resistant analogue teduglutide are trophic for the gastrointestinal epithelium. Exposure increases villus height and crypt size and results in increased overall intestinal weight. As these effects may be mediated through stimulation of the stem cell compartment, they may promote intestinal healing and act as potential anti-mucositis agents in patients undergoing cancer chemotherapy. A study was initiated to investigate the protective effects of teduglutide on the murine small intestinal epithelium following gamma-irradiation using the crypt microcolony assay as a measure of stem cell survival and functional competence. Teduglutide demonstrated intestinotrophic effects in both CD1 and BDF1 mouse strains. In BDF1 mice, subcutaneous injection of GLP-2 or teduglutide (0.2 mg/kg/day, b.i.d.) for 14 days increased intestinal weight by 28% and resulted in comparable increases in crypt size, villus height and area. Teduglutide given daily for 6 or 14 days prior to whole body, gamma-irradiation significantly increased crypt stem cell survival when compared with vehicle-treated controls. The mean levels of protection over a range of doses provided protection factors from 1.3 to 1.5. A protective effect was only observed when teduglutide was given before irradiation. These results suggest that teduglutide has the ability to modulate clonogenic stem cell survival in the small intestine and this may have a useful clinical application in the prevention of cancer therapy-induced mucositis.
Booth
C
C
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Booth
D
D
Williamson
S
S
Demchyshyn
L L
LL
Potten
C S
CS
D000818:Animals; D001681:Biological Assay; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects; D053767:Glucagon-Like Peptide 2; D004763:Glucagon-Like Peptides; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D010455:Peptides / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011878:Radiotherapy / Q000009:adverse effects; D013234:Stem Cells / Q000187:drug effects* / Q000528:radiation effects
D053767:Glucagon-Like Peptide 2; D010455:Peptides; D011837:Radiation-Protective Agents; D004763:Glucagon-Like Peptides; C494910:teduglutide