Potten C S, Booth D, Haley J D
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Br J Cancer. 1997;75(10):1454-9. doi: 10.1038/bjc.1997.249.
The gastrointestinal tract, with its rapid cell replacement, is sensitive to cytotoxic damage and can be a site of dose-limiting toxicity in cancer therapy. Here, we have investigated the use of one growth modulator to manipulate the cell cycle status of gastrointestinal stem cells before cytotoxic exposure to minimize damage to this normal tissue. Transforming growth factor beta-3 (TGF-beta3), a known inhibitor of cell cycle progression through G1, was used to alter intestinal crypt stem cell sensitivity before 12-16 Gy of gamma irradiation, which was used as a model cytotoxic agent. Using a crypt microcolony assay as a measure of functional competence of gastrointestinal stem cells, it was shown that the administration of TGF-beta3 over a 24-h period before irradiation increased the number of surviving crypts by four- to six-fold. To test whether changes in crypt survival are reflected in the well-being of the animal, survival time analyses were performed. After 14.5 Gy of radiation, only 35% of the animals survived within a period of about 12 days, while prior treatment with TGF-beta3 provided significant protection against this early gastrointestinal animal death, with 95% of the treated animals surviving for greater than 30 days.
胃肠道由于其细胞快速更替，对细胞毒性损伤敏感，在癌症治疗中可能成为剂量限制毒性的发生部位。在此，我们研究了使用一种生长调节剂在细胞毒性暴露前调控胃肠道干细胞的细胞周期状态，以尽量减少对这种正常组织的损伤。转化生长因子β-3（TGF-β3）是一种已知的通过G1期抑制细胞周期进程的物质，在12 - 16 Gy的γ射线照射前用于改变肠道隐窝干细胞的敏感性，γ射线用作细胞毒性剂模型。使用隐窝微集落测定法作为胃肠道干细胞功能活性的衡量指标，结果显示在照射前24小时给予TGF-β3可使存活的隐窝数量增加4至6倍。为了测试隐窝存活的变化是否反映在动物的健康状况上，进行了生存时间分析。接受14.5 Gy辐射后，在约12天内只有35%的动物存活，而预先用TGF-β3治疗可显著预防早期胃肠道动物死亡，95%的治疗动物存活超过30天。
