Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells.
Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells.
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DOI：
10.1182/blood.v89.9.3345
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发表时间：
1997-05
期刊：
影响因子：
20.3
通讯作者：
G. Chen;X. Shi;W. Tang;S. Xiong;J. Zhu;X. Cai;Z. Han;J. Ni;G. Shi;P. Jia;M. M. Liu-M.-M.
中科院分区：
文献类型：
--
作者：
G. Chen;X. Shi;W. Tang;S. Xiong;J. Zhu;X. Cai;Z. Han;J. Ni;G. Shi;P. Jia;M. M. Liu-M.-M.
近年来国内临床研究表明，三氧化二砷是治疗急性早幼粒细胞白血病（APL）的有效药物，且相对安全。我们以前发现As_2O_3可诱导APL细胞株NB_4细胞凋亡，其机制与下调bcl-2基因表达和调节PML-RAR α嵌合蛋白有关。为了进一步了解这种替代疗法的APL的机制，我们在这份报告中调查了广泛的浓度范围内的As 2 O2对培养的原代APL细胞，全反式维甲酸（ATRA）敏感（NB 4细胞）和ATRA耐药（MR 2亚克隆）APL细胞系的影响。结果表明，As_2O_3对APL细胞具有剂量依赖性的双重作用：高浓度（0.5 ~ 2 μ mol/L）时优先诱导凋亡，低浓度（0.1 ~ 0.5 μ mol/L）时诱导部分分化。0.1 ~ 2 μ mol/L的As_2O_3对PML-RAR α蛋白的快速调节和降解可能是这两种效应的原因之一。骨髓和外周血检查表明，髓样细胞，可能是由于部分在体内分化，和变性细胞增加后2至3周的连续治疗在体内As 2 O3白血病早幼粒细胞减少。结论：诱导凋亡和部分分化可能是As 2 O3治疗APL的主要机制，PML-RAR α可能在As 2 O3治疗APL的特异性作用中起重要作用。
Recent clinical studies in China showed that As2O3 is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL). We found previously that As2O3 can trigger apoptosis of APL cell line NB4 cells, which is associated with downregulation of bcl-2 gene expression and modulation of PML-RAR alpha chimeric protein. To further understand the mechanisms of this alternative therapy for APL, we investigated in this report the effects of a wide range of concentrations of As2O2 on cultured primary APL cells, all-trans retinoic acid (ATRA)-susceptible (NB4 cells) and ATRA-resistant (MR2 subclone) APL cell lines. The results indicated that As2O3 had dose-dependent dual effects on APL cells: inducing preferentially apoptosis at relatively high concentrations (0.5 to 2 micromol/L) and inducing partial differentiation at low concentrations (0.1 to 0.5 micromol/L). The rapid modulation and degradation of PML-RAR alpha proteins, which was induced by As2O3 at 0.1 to 2 micromol/L, could contribute to these two effects. Bone marrow and peripheral blood examination showed that myelocyte-like cells, probably as a result of partial in vivo differentiation, and degenerative cells increased after 2 to 3 weeks of continuous in vivo As2O3 treatment when leukemic promyelocytes decreased. In conclusion, combination of induction of apoptosis and partial differention could be the main cellular mechanisms of As2O3 in the treatment of APL, and PML-RAR alpha could play an important role in determining the specific effects of As2O3 on APL cells.