Kabaya K, Akahori H, Shibuya K, Nitta Y, Ida M, Kusaka M, Kato T, Miyazaki H
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Stem Cells. 1996 Nov;14(6):651-60. doi: 10.1002/stem.140651.
The in vivo effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated molecule of recombinant human thrombopoietin modified with polyethylene glycol, were investigated in normal Balb/c mice. PEG-rHuMGDF was more potent in producing platelets and the dose-response curve was steeper compared with the case of the nonpegylated form of this molecule. Five consecutive injections with PEG-rHuMGDF caused a dose-dependent increase in peripheral platelet counts with a peak on day 8. There was a dose-dependent rise in platelet counts on day 8 at daily doses from 0.333 to 30 micrograms/kg. Intermediate doses of PEG-rHuMGDF (1.111 to 10 micrograms/kg/day) caused a significant decrease in mean platelet volume, and conversely, higher doses of PEG-rHuMGDF (30 to 270 micrograms/kg/day) induced a dose-dependent increase in mean platelet volume. There was a dose-dependent decrease in hemoglobin concentration with a minimum on day 8 but no significant reduction in reticulocyte counts following PEG-rHuMGDF administration. White blood cell counts were unchanged by PEG-rHuMGDF treatment. Marrow megakaryocyte size enlarged to 1.5-fold and the number of marrow megakaryocytes increased to sixfold by consecutive administration of PEG-rHuMGDF at 30 micrograms/kg/day. A twofold increase in the number of marrow megakaryocytic progenitor cells (colony-forming units-megakaryocyte) was also observed. Marrow erythroid progenitor (colony-forming units-erythroid) counts decreased but splenic colony-forming units-erythroid, marrow and splenic erythro/myeloid progenitor cell counts, and splenic granulocyte/macrophage progenitor cell counts increased with PEG-rHuMGDF treatment. Marrow and splenic erythroid burst-forming cells were unchanged. These results indicate that PEG-rHuMGDF, a truncated molecule of thrombopoietin, is a potent stimulator for megakaryopoiesis and thrombopoiesis, and also affects the development of other hematopoietic cells in normal mice.
聚乙二醇化重组人巨核细胞生长和发育因子（PEG-rHuMGDF）是一种经聚乙二醇修饰的重组人血小板生成素截短分子，本研究在正常Balb/c小鼠中考察了其体内效应。与该分子的非聚乙二醇化形式相比，PEG-rHuMGDF在产生血小板方面更有效，且剂量-反应曲线更陡峭。连续5次注射PEG-rHuMGDF导致外周血小板计数呈剂量依赖性增加，在第8天达到峰值。在每日剂量为0.333至30微克/千克时，第8天血小板计数呈剂量依赖性上升。中等剂量的PEG-rHuMGDF（1.111至10微克/千克/天）导致平均血小板体积显著降低，相反，较高剂量的PEG-rHuMGDF（30至270微克/千克/天）诱导平均血小板体积呈剂量依赖性增加。血红蛋白浓度呈剂量依赖性降低，在第8天降至最低，但给予PEG-rHuMGDF后网织红细胞计数无显著降低。PEG-rHuMGDF治疗对白细胞计数无影响。连续给予30微克/千克/天的PEG-rHuMGDF可使骨髓巨核细胞大小增大至1.5倍，骨髓巨核细胞数量增加至6倍。还观察到骨髓巨核细胞祖细胞（集落形成单位-巨核细胞）数量增加了两倍。骨髓红系祖细胞（集落形成单位-红系）计数减少，但脾集落形成单位-红系、骨髓和脾红系/髓系祖细胞计数以及脾粒细胞/巨噬细胞祖细胞计数在PEG-rHuMGDF治疗后增加。骨髓和脾红系爆式集落形成细胞未发生变化。这些结果表明，血小板生成素截短分子PEG-rHuMGDF是巨核细胞生成和血小板生成的有效刺激剂，并且还影响正常小鼠中其他造血细胞的发育。
