Granulocyte colony-stimulating factor enhances bone marrow stem cell damage caused by repeated administration of cytotoxic agents
Granulocyte colony-stimulating factor enhances bone marrow stem cell damage caused by repeated administration of cytotoxic agents
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DOI：
10.1182/blood.v92.6.1950.418k21_1950_1956
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发表时间：
1998-09-15
期刊：
影响因子：
20.3
通讯作者：
Mauch, PM
中科院分区：
文献类型：
--
作者：
van Os, R;Robinson, S;Mauch, PM
尽管越来越多地使用细胞因子来规避癌症治疗的急性剂量限制性髓毒性，但细胞毒性药物和细胞因子对负责长期造血的原始干细胞的联合作用知之甚少。在实验模型中，我们对C57BL/6 （B6）小鼠的原始干细胞施用具有不同作用的细胞毒性药物。小鼠每隔一周接受6次剂量的环磷酰胺（CY, 84 mg/kg）、VP-16 (24 mg/kg) +顺铂（2.4 mg/kg）、碳铂（50 mg/kg）、氯苯（12 mg/kg）、BCNU （13.2 mg/kg）或TBI （80 cGy）。每次给药后第3 ~ 6天，每日皮下两次给予粒细胞集落刺激因子（g - csf； 250 μ g/kg/天）。与单独使用细胞毒剂的动物进行比较，探讨G-CSF对长期造血的影响。在最后一次给药后20周，通过评估外周血计数、骨髓细胞数量、祖细胞含量（集落形成单位-脾脏；CFU-S）和原始干细胞数量（长期再生能力和第28天和第35天的鹅卵石区形成细胞[CAFC]频率）来测量造血功能。在给予碳铂、氯苯、BCNU和TBI的动物中，单独暴露于细胞毒性药物会导致原始干细胞的显著减少（通过重新填充单位[RU]和第28天和第35天的CAFC含量来测量），但在使用环磷酰胺或VP-16和顺铂的动物中则没有。与不给G-CSF的动物相比，添加G-CSF的动物在使用氯苯、BCNU或TBI时，干细胞含量显著降低。因此，在反复暴露于细胞毒性药物后给予G-CSF，当与已知损伤原始干细胞的药物联合使用时，似乎会损伤原始干细胞室。这些结果虽然是在实验模型中获得的，但应该引起人们对临床中滥用G-CSF的关注。(C) 1998年由美国血液病学会出版。
Despite the increasing use of cytokines to circumvent the acute dose-limiting myelotoxicity of cancer treatment, little is known about the combined effects of cytotoxic agents and cytokines on the primitive stem cells responsible for longterm hematopoiesis. In an experimental model, we administered cytotoxic agents that have variable effects on primitive stem cells in C57BL/6 (B6)-mice. Mice received six every-other-week doses of cyclophosphamide (CY, 84 mg/kg), VP-16 (24 mg/kg) + cisplatinum (2.4 mg/kg), carboplatinum (50 mg/kg), chlorambucil (12 mg/kg), BCNU (13.2 mg/kg), or TBI (80 cGy). Granulocyte colony-stimulating factor (G-CSF; 250 mu g/kg/day) was administered subcutaneously twice daily on days 3 to 6 after each dose of the cytotoxic agent. Comparison with animals receiving the cytotoxic agent alone was made to investigate the effects of G-CSF on long-term hematopoiesis. Hematopoiesis was measured 20 weeks after the last dose of the cytotoxic agent by assessment of peripheral blood counts, marrow cellularity, progenitor cell content (colony-forming units-spleen; CFU-S), and primitive stem cell number (long-term repopulating ability and day 28 and day 35 cobblestone area-forming cell [CAFC] frequencies). Exposure to cytotoxic agents alone resulted in a significant decrease in primitive stem cells (as measured by repopulating units [RU] and day 28 and day 35 CAFC content) in animals given carboplatinum, chlorambucil, BCNU, and TBI, but not in animals treated with cyclophosphamide or VP-16 and cisplatinum. The addition of G-CSF resulted in a significant decrease in stem cell content when compared with no G-CSF administration in animals treated with chlorambucil, BCNU, or TBI. Thus, G-CSF administered after repeated exposure to cytotoxic agents, appeared to damage the primitive stem cell compartment when used in combination with agents known to damage primitive stem cells. These results, although obtained in an experimental model, should raise concerns for the indiscriminate use of G-CSF in the clinic. (C) 1998 by The American Society of Hematology.