Chen G Q, Shi X G, Tang W, Xiong S M, Zhu J, Cai X, Han Z G, Ni J H, Shi G Y, Jia P M, Liu M M, He K L, Niu C, Ma J, Zhang P, Zhang T D, Paul P, Naoe T, Kitamura K, Miller W, Waxman S, Wang Z Y, de The H, Chen S J, Chen Z
Shanghai Institute of Hematology, Samuel Waxman Cancer Research Foundation Lab, Rui-Jin Hospital, China.
Blood. 1997 May 1;89(9):3345-53.
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.
中国最近的临床研究表明，三氧化二砷是治疗急性早幼粒细胞白血病（APL）的一种有效且相对安全的药物。我们先前发现，三氧化二砷可诱导APL细胞系NB4细胞凋亡，这与bcl-2基因表达下调及PML-RARα嵌合蛋白的调节有关。为进一步了解这种APL替代疗法的机制，我们在本报告中研究了不同浓度的三氧化二砷对培养的原代APL细胞、全反式维甲酸（ATRA）敏感（NB4细胞）和ATRA耐药（MR2亚克隆）的APL细胞系的影响。结果表明，三氧化二砷对APL细胞具有剂量依赖性双重作用：在相对高浓度（0.5至2微摩尔/升）时优先诱导凋亡，在低浓度（0.1至0.5微摩尔/升）时诱导部分分化。三氧化二砷在0.1至2微摩尔/升浓度下诱导的PML-RARα蛋白的快速调节和降解可能促成了这两种作用。骨髓和外周血检查显示，连续进行三氧化二砷体内治疗2至3周后，当白血病早幼粒细胞减少时，可能由于部分体内分化产生的髓样细胞样细胞和退变细胞增加。总之，诱导凋亡和部分分化的联合作用可能是三氧化二砷治疗APL的主要细胞机制，而PML-RARα可能在决定三氧化二砷对APL细胞的特定作用中发挥重要作用。
