Spiga M G, Weidner D A, Trentesaux C, LeBoeuf R D, Sommadossi J P
Department of Biochemistry and Molecular Biology, School of Medicine, University of Miami, FL 33136, USA.
Antiviral Res. 1999 Dec 31;44(3):167-77. doi: 10.1016/s0166-3542(99)00065-0.
3'-Azido-3'-deoxythymidine (AZT) treatment in HIV-infected patients is limited by bone marrow suppression including neutropenia and anemia. Previous studies had shown a direct effect of high concentrations of this drug on globin gene expression in K-562 erythroleukemia cells. To better define the mechanism(s) of AZT-induced bone marrow toxicity, the present study evaluates these effects in more relevant human erythroid progenitor liquid cultures, because AZT is 100 times more toxic to human bone marrow cells than K-562 cells. At a clinically relevant concentration of 1 microM, AZT inhibited specifically erythroid cell growth by approximately 58% as compared with untreated cells. The percentage of cells synthesizing hemoglobin was decreased also by 47% in AZT-treated cells with beta-globin mRNA levels accounting for 0.27 pmol in treated cells as compared with 1.44 under control conditions while beta-actin levels remained unchanged. Under the same conditions, AZT inhibited the beta-globin chain synthesis by approximately 60% as compared with the control. Consistent with the data described above was the finding that a concentration as low as 0.1 microM of AZT decreased by almost 40% the binding level of the erythroid-specific transcription factor GATA-1. These findings demonstrate that AZT, at clinical relevant concentrations, specifically inhibits beta-globin gene expression in human erythroid progenitor liquid cell culture.
对感染HIV的患者使用3'-叠氮基-3'-脱氧胸苷（AZT）进行治疗时，会受到包括中性粒细胞减少和贫血在内的骨髓抑制作用的限制。先前的研究表明，高浓度的这种药物对K-562红白血病细胞中的珠蛋白基因表达有直接影响。为了更好地确定AZT诱导骨髓毒性的机制，本研究在更具相关性的人类红系祖细胞液体培养中评估了这些影响，因为AZT对人类骨髓细胞的毒性比对K-562细胞的毒性高100倍。在1 microM的临床相关浓度下，与未处理的细胞相比，AZT特异性地抑制了红系细胞生长约58%。在经AZT处理的细胞中，合成血红蛋白的细胞百分比也降低了47%，与对照条件下的1.44相比，处理细胞中的β-珠蛋白mRNA水平为0.27 pmol，而β-肌动蛋白水平保持不变。在相同条件下，与对照相比，AZT抑制β-珠蛋白链合成约60%。与上述数据一致的是，发现低至0.1 microM的AZT浓度使红系特异性转录因子GATA-1的结合水平降低了近40%。这些发现表明，在临床相关浓度下，AZT特异性地抑制人类红系祖细胞液体细胞培养中的β-珠蛋白基因表达。
