Bhalla K, Birkhofer M, Grant S, Graham G
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York.
Exp Hematol. 1989 Jan;17(1):17-20.
Administration of 3'-azido-3'-deoxythymidine (AZT) to patients with acquired immunodeficiency syndrome (AIDS) causes significant anemia and neutropenia. The bone marrow cytotoxicity of AZT has been attributed to deoxyribonucleotide pool perturbations that might result in impaired DNA synthesis in normal bone marrow elements. We examined the effect of human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) on AZT-mediated biochemical perturbations and in vitro growth inhibition of normal bone marrow myeloid progenitor cells. Exposure of nonadherent, bone marrow mononuclear cells (BMMC) to 100 ng/ml of rGM-CSF for 6 h resulted in approximately twofold increments in the mean intracellular deoxycytidine triphosphate (dCTP) and thymidine triphosphate (dTTP) levels. Administration of 10 microM AZT alone to BMMC for 6 h markedly reduced dCTP and dTTP levels and generated significant levels of AZT triphosphate (AZT-TP). Coadministration of rGM-CSF (100 ng/ml) along with AZT (10 microM) partly restored dCTP and dTTP levels and significantly reduced AZT-TP levels. Furthermore, simultaneous exposure of BMMC for 4 h to 100 ng/ml of rGM-CSF reduced the mean DNA incorporation of [3H]AZT (10 microM) from 27.2 to 19.1 pmol/micrograms of DNA. Additionally, the inhibitory effects of AZT (10 microM) on granulocyte-macrophage colony-forming unit (CFU-GM) colony growth were significantly reduced in the presence of 100 ng/ml of rGM-CSF. These in vitro studies suggest that rGM-CSF partly corrects AZT-mediated biochemical perturbations as well as reduces the cytotoxicity of AZT in normal human bone marrow myeloid progenitor cells.
给获得性免疫缺陷综合征（AIDS）患者使用3'-叠氮-3'-脱氧胸苷（AZT）会导致严重的贫血和中性粒细胞减少。AZT的骨髓细胞毒性归因于脱氧核苷酸池的紊乱，这可能导致正常骨髓细胞中的DNA合成受损。我们研究了重组人粒细胞-巨噬细胞集落刺激因子（rGM-CSF）对AZT介导的生化紊乱以及对正常骨髓髓系祖细胞体外生长抑制的影响。将非贴壁骨髓单个核细胞（BMMC）暴露于100 ng/ml的rGM-CSF中6小时，导致细胞内脱氧胞苷三磷酸（dCTP）和胸苷三磷酸（dTTP）的平均水平增加约两倍。单独给BMMC使用10 μM的AZT 6小时，显著降低了dCTP和dTTP水平，并产生了大量的三磷酸AZT（AZT-TP）。rGM-CSF（100 ng/ml）与AZT（10 μM）共同给药部分恢复了dCTP和dTTP水平，并显著降低了AZT-TP水平。此外，BMMC同时暴露于100 ng/ml的rGM-CSF中4小时，使[3H]AZT（10 μM）的平均DNA掺入量从27.2降至19.1 pmol/μg DNA。此外，在存在100 ng/ml的rGM-CSF时，AZT（10 μM）对粒细胞-巨噬细胞集落形成单位（CFU-GM）集落生长的抑制作用显著降低。这些体外研究表明，rGM-CSF可部分纠正AZT介导的生化紊乱，并降低AZT对正常人骨髓髓系祖细胞的细胞毒性。
