Neelis K J, Dubbelman Y D, Qingliang L, Thomas G R, Eaton D L, Wagemaker G
Institute of Hematology, Erasmus Universiteit Rotterdam, The Netherlands.
Exp Hematol. 1997 Sep;25(10):1084-93.
Simultaneous treatment with human thrombopoietin (TPO) and granulocyte colony-stimulating factor (G-CSF) was evaluated in a placebo-controlled rhesus monkey study using 5 Gy total body irradiation (TBI) to induce 3 weeks of pancytopenia. Daily administration of TPO (10 microg/kg/day injected subcutaneously [sc] days 1-21 after TBI) promoted platelet and reticulocyte recovery, resulting in less profound nadirs and a rapid recovery to normal levels. Platelet transfusions were not required in these animals, in contrast to controls, and hemoglobin levels stabilized rapidly. TPO treatment did not influence neutrophil counts. G-CSF (5 microg/kg/day sc days 1-21) stimulated neutrophil regeneration and had no effect on platelet levels. Simultaneous treatment with TPO and G-CSF was as effective as treatment with TPO alone in preventing thrombocytopenia, although with the former regimen platelet levels did not rise to the supranormal levels seen with the latter. Neutrophil recovery was greatly augmented compared with G-CSF treatment alone, resulting in a less profound nadir and a recovery that started much earlier, as did monocyte, CD11b+, CD16+, and CD56+ cell reconstitution. In addition, TPO strongly promoted the recovery of bone marrow cellularity and granulocyte/macrophage and erythroid progenitor cells: The number of bone marrow CD34+ cells was greater by two orders of magnitude in TPO-treated animals than in controls in the second week of treatment, whereas G-CSF by itself had no influence. In the third week after TBI an elevation of LDH1 values was observed in TPO-treated monkeys concurrent with normoblastosis; both of these findings were attributed to rapid erythropoiesis. TPO had no effect on hemostasis parameters. Adverse TPO and/or G-CSF effects were not observed. This study demonstrates that simultaneous TPO and G-CSF treatment after cytoreductive treatment prevents thrombocytopenia, accelerates platelet and red cell reconstitution, alleviates neutropenia, and promotes the recovery of immature bone marrow cells. The effect on CD34+ GM progenitor cells may explain the augmented G-CSF responses in TPO-treated monkeys; it also suggests that TPO may become a key growth factor in the design of treatment regimens to accelerate both immature bone marrow and mature blood cell reconstitution after cytoreductive therapy.
在一项安慰剂对照的恒河猴研究中，评估了人血小板生成素（TPO）和粒细胞集落刺激因子（G-CSF）联合治疗的效果。该研究使用5 Gy全身照射（TBI）诱导3周的全血细胞减少。每天给予TPO（TBI后第1 - 21天皮下注射10μg/kg/天）可促进血小板和网织红细胞的恢复，使最低点不那么严重，并能快速恢复到正常水平。与对照组相比，这些动物无需进行血小板输注，血红蛋白水平也迅速稳定。TPO治疗对中性粒细胞计数没有影响。G-CSF（第1 - 21天皮下注射5μg/kg/天）刺激中性粒细胞再生，对血小板水平无影响。TPO和G-CSF联合治疗在预防血小板减少方面与单独使用TPO治疗效果相同，尽管在前一种方案中血小板水平未升至后一种方案所见的超正常水平。与单独使用G-CSF治疗相比，中性粒细胞的恢复显著增强，最低点不那么严重，恢复开始得更早，单核细胞、CD11b +、CD16 +和CD56 +细胞的重建也是如此。此外，TPO强烈促进骨髓细胞数量以及粒细胞/巨噬细胞和红系祖细胞的恢复：在治疗的第二周，TPO治疗的动物骨髓CD34 +细胞数量比对照组多两个数量级，而G-CSF单独使用则无影响。在TBI后的第三周，TPO治疗的猴子中观察到乳酸脱氢酶1（LDH1）值升高，同时出现幼红细胞增多；这两个发现都归因于快速的红细胞生成。TPO对止血参数没有影响。未观察到TPO和/或G-CSF的不良影响。这项研究表明，细胞减灭性治疗后同时使用TPO和G-CSF可预防血小板减少，加速血小板和红细胞重建，减轻中性粒细胞减少，并促进未成熟骨髓细胞的恢复。对CD34 +粒系祖细胞的作用可能解释了TPO治疗的猴子中G-CSF反应增强的原因；这也表明TPO可能成为设计治疗方案的关键生长因子，以加速细胞减灭性治疗后未成熟骨髓和成熟血细胞的重建。
