Booth C, Booth D, Williamson S, Demchyshyn L L, Potten C S
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Cell Prolif. 2004 Dec;37(6):385-400. doi: 10.1111/j.1365-2184.2004.00320.x.
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.
胰高血糖素样肽-2及其抗二肽基肽酶（DP-IV）类似物替度鲁肽对胃肠道上皮具有营养作用。接触后可增加绒毛高度和隐窝大小，并导致肠道整体重量增加。由于这些作用可能是通过刺激干细胞区室介导的，它们可能促进肠道愈合，并在接受癌症化疗的患者中作为潜在的抗粘膜炎药物。启动了一项研究，使用隐窝微集落测定法作为干细胞存活和功能能力的指标，来研究替度鲁肽对γ射线照射后小鼠小肠上皮的保护作用。替度鲁肽在CD1和BDF1小鼠品系中均表现出肠营养作用。在BDF1小鼠中，皮下注射GLP-2或替度鲁肽（0.2mg/kg/天，每日两次）14天，可使肠道重量增加28%，并导致隐窝大小、绒毛高度和面积有类似增加。在全身γ射线照射前6天或14天每天给予替度鲁肽，与载体处理的对照组相比，可显著提高隐窝干细胞存活率。一系列剂量的平均保护水平提供了1.3至1.5的保护因子。仅在照射前给予替度鲁肽时才观察到保护作用。这些结果表明替度鲁肽有能力调节小肠中克隆形成干细胞的存活，这在预防癌症治疗引起的粘膜炎方面可能有有用的临床应用。
