Scheding S, Media J E, Nakeff A
Division of Hematology and Oncology, Wayne State University, School of Medicine, Detroit, MI 48201.
Exp Hematol. 1994 Jan;22(1):60-5.
The immediate hematopoietic response to 3'-azido-3'-deoxythymidine (AZT) was characterized in an unperturbed and regenerating mouse marrow model to identify the in vivo hematopoietic targets of AZT and test whether AZT toxicity is dependent on the proliferative activity of the hematopoietic targets. B6D2F1 mice received intravenous (IV) bolus injections of 30, 60, 120, and 240 mg/kg AZT. None of the doses induced consistent changes in the number of hematopoietic stem and progenitor cells. However, identical cumulative doses administered as an intravenous 24-hour infusion led to marked changes. Spleen colony-forming units (CFU-S) per femur were diminished to about 60%. Burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E) were substantially reduced to about 15 to 35% at the two highest doses, whereas the femoral content of colony-forming units-granulocyte/macrophage (CFU-GM) and colony-forming units-megakaryocyte (CFU-Meg) was unchanged. When administered to mice whose marrow was regenerating from total-body irradiation (TBI) and subsequent bone marrow transplantation (high proliferative fraction), 240 mg/kg AZT caused considerable reductions of all hematopoietic cell stages even when given as a single IV injection. The results indicate that (1) the mode of application is critical for AZT hematotoxicity; (2) erythropoietic progenitors are the most sensitive to AZT toxicity; and (3) hematotoxicity increases with increasing proliferative activity.
在未受干扰和再生的小鼠骨髓模型中，对3'-叠氮基-3'-脱氧胸苷（AZT）的即时造血反应进行了表征，以确定AZT在体内的造血靶点，并测试AZT毒性是否取决于造血靶点的增殖活性。B6D2F1小鼠静脉推注30、60、120和240mg/kg的AZT。这些剂量均未引起造血干细胞和祖细胞数量的一致变化。然而，以静脉内24小时输注方式给予相同的累积剂量会导致明显变化。每根股骨的脾集落形成单位（CFU-S）减少至约60%。在两个最高剂量下，红系爆式集落形成单位（BFU-E）和红系集落形成单位（CFU-E）大幅减少至约15%至35%，而粒细胞/巨噬细胞集落形成单位（CFU-GM）和巨核细胞集落形成单位（CFU-Meg）的股骨含量未发生变化。当给予经全身照射（TBI）和随后骨髓移植后骨髓正在再生的小鼠（高增殖分数）时，即使单次静脉注射240mg/kg的AZT也会导致所有造血细胞阶段显著减少。结果表明：（1）给药方式对AZT的血液毒性至关重要；（2）红系祖细胞对AZT毒性最敏感；（3）血液毒性随增殖活性的增加而增加。
