Khan W B, Shui C, Ning S, Knox S J
Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5105, USA.
Radiat Res. 1997 Sep;148(3):248-53.
Radiation-induced gastrointestinal toxicity is due in part to the killing of the clonogenic crypt cells and eventual depopulation of the villi. Keratinocyte growth factor (KGF), a member of the fibroblast growth factor family (FGF-7), has been shown to stimulate proliferation of cells along the murine digestive tract from the foregut to the colon. Using an in vivo microcolony assay, we found that 1.0 mg/kg KGF administered intravenously (i.v.) for 3 consecutive days (2 days before, 1 day before and 2 h after irradiation) increased the number of surviving crypts by a factor of 2.6, 2.7 and 2.4 in the duodenum, jejunum and ileum, respectively, after a single-dose whole-body irradiation (10-16 Gy) (P < 0.001). Treatment of mice with KGF i.v. significantly increased the D0 of the radiation survival curves by 0.37, 0.22 and 0.36 Gy, leading to dose modification factors of 1.28, 1.16 and 1.24 for duodenal, jejunal and ileal crypt cells, respectively. Similar results were obtained with KGF administered subcutaneously. Treatment with both KGF and stem cell factor (previously shown to enhance intestinal crypt survival after total-body irradiation) increased the number of surviving crypt cells after irradiation to levels similar to that in animals treated with KGF alone. Administration of KGF for 7 consecutive days (beginning 2 days prior to irradiation) increased the LD(50/10) from 5.50 Gy/day to 5.90 Gy/day (P = 0.05) for animals irradiated with five daily fractions to a local abdominal field. These results suggest that KGF may be of clinical value in reducing radiation toxicity to the intestine.
辐射诱导的胃肠道毒性部分归因于克隆性隐窝细胞的死亡以及绒毛最终的细胞缺失。角质形成细胞生长因子（KGF）是成纤维细胞生长因子家族（FGF - 7）的成员，已被证明能刺激从鼠类前肠到结肠的整个消化道细胞的增殖。通过体内微克隆试验，我们发现，在单次全身照射（10 - 16 Gy）后，连续3天静脉注射（i.v.）1.0 mg/kg KGF（照射前2天、前1天以及照射后2小时各注射一次），可使十二指肠、空肠和回肠中存活隐窝的数量分别增加2.6倍、2.7倍和2.4倍（P < 0.001）。静脉注射KGF治疗小鼠显著提高了辐射存活曲线的D0值，分别增加了0.37 Gy、0.22 Gy和0.36 Gy，导致十二指肠、空肠和回肠隐窝细胞的剂量修正因子分别为1.28、1.16和1.24。皮下注射KGF也得到了类似结果。同时使用KGF和干细胞因子（先前已证明其可增强全身照射后肠道隐窝的存活）进行治疗，照射后存活隐窝细胞的数量增加至与单独使用KGF治疗的动物相似的水平。对于局部腹部野接受每日5次分割照射的动物，连续7天（从照射前2天开始）给予KGF可使LD(50/10)从5.50 Gy/天提高至5.90 Gy/天（P = 0.05）。这些结果表明，KGF在减轻肠道辐射毒性方面可能具有临床价值。
