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. 2004 Dec;37(6):385-400.
doi: 10.1111/j.1365-2184.2004.00320.x.

Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage

C Booth  1 , D Booth, S Williamson, L L Demchyshyn, C S Potten
Affiliations

Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage

C Booth et al. Cell Prolif. 2004 Dec.

Abstract

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.

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Figures

Figure 1
Figure 1
Effects of GLP‐2 and teduglutide on small intestinal weight in CD1 and BDF1 mice. Effects on small intestinal weight in CD1 and BDF1 mice following administration of teduglutide or GLP‐2 by s.c. injection (0.1 mg/kg/injection, G.i.d.) for 14 days. Values represent the per cent change compared with saline‐treated controls.
Figure 2
Figure 2
Morphological effects of GLP‐2 and teduglutide in CD1 and BDF1 mice. The effects on villus area (a), villus height (b), crypt area (c) and crypt height (d) in CD1 mice and BDF1 mice following treatment with either teduglutide or GLP‐2. The data were obtained by determining the changes in the parameters relative (percentages) to saline‐treated control animals. Teduglutide or GLP‐2 was administered by s.c. injection (0.1 mg/kg/injection, G.i.d.) for 14 days.
Figure 3
Figure 3
Crypt survival following irradiation in vehicle‐treated and control animal groups. Crypt survival curves determined on day 4 following 14‐day pre‐treatment, 14‐day pre‐treatment and 4‐day post‐, 4 day post‐irradiation (a), 6‐day pre‐treatment, 6‐day pre‐treatment and 4‐day post‐irradiation (b) with saline (i.e. vehicle controls) and for animals receiving no treatment at all (irradiation alone). Each point represents mean ± SEM of six mice. The parameters defining these survival curves are presented in Table 2.
Figure 4
Figure 4
Crypt survival following 14‐day treatment with teduglutide prior to irradiation. Crypt survival curves in BDF1 mice administered teduglutide by s.c. injection (0.2 mg/kg/day) b.i.d. for 14 days prior to exposure to doses of irradiation ranging from 11 to 16 Gy. Teduglutide significantly increased crypt stem cell survival compared with vehicle controls (P < 0.001). Each point represents mean ± SEM of six mice. The Do and N‐values for these curves are shown in Table 2.
Figure 5
Figure 5
Crypt survival following 6‐day treatment with teduglutide prior to irradiation. Crypt survival curves in BDF1 mice administered teduglutide by s.c. injection (0.2 mg/kg/day, b.i.d.) for 6 days prior to exposure to doses of irradiation ranging from 11 to 16 Gy. Teduglutide significantly increased crypt stem cell survival compared with vehicle controls (P < 0.001). Each point represents mean ± SEM of six mice. The Do and N‐values for these curves are shown in Table 2.
Figure 6
Figure 6
Crypt survival following 6‐day pre‐treatment and 4‐day post‐irradiation treatment with teduglutide. Crypt survival curves in BDF1 mice administered teduglutide by s.c. injection (0.2 mg/kg/day, b.i.d) for 6 days prior to and 4 days following exposure to doses of irradiation ranging from 11 to 16 Gy. Teduglutide significantly increased crypt stem cell survival compared with vehicle controls (P < 0.001). Each point represents mean ± SEM of six mice. The Do and N‐values for these curves are shown in Table 2.
Figure 7
Figure 7
Crypt survival following 14‐day pre‐treatment and 4‐day post‐irradiation treatment with teduglutide. Crypt survival curves in BDF1 mice administered teduglutide by s.c. injection (0.2 mg/kg/day, b.i.d.) for 14 days prior to and 4 days following exposure to doses of irradiation ranging from 11 to 16 Gy. Teduglutide did not increase crypt stem cell survival compared with vehicle controls (P < 0.31). Each point represents mean ± SEM of six mice. The Do values for these curves are shown in Table 2.
Figure 8
Figure 8
Crypt survival following 4‐day treatment with teduglutide following irradiation. Crypt survival curves in BDF1 mice administered teduglutide by s.c. injection (0.2 mg/kg/day) b.i.d. for 4 days following exposure to doses of irradiation ranging from 11 to 16 Gy. Teduglutide did not increase crypt stem cell survival compared with vehicle controls (P < 0.69). Each point represents mean ± SEM of six mice. The Do values for these curves are shown in Table 2.
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