Alemany M, Levin J
Institut des Vaisseaux et du Sang, Hôpital Lariboisière, Paris, France.
Leuk Lymphoma. 2000 Jun;38(1-2):153-63. doi: 10.3109/10428190009060329.
Arsenic trioxide (As2O3) has been demonstrated to be effective for the treatment of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce apoptosis in the APL cell line NB4. The effect of this newly utilized chemotherapeutic agent on other lineages is currently under study to evaluate its efficacy for the treatment of other human malignancies and myeloproliferative syndromes. A recent study described the effects of As2O3 upon viability, proliferation, and induction of apoptosis in four different megakaryocytic leukemia cell lines. At pharmacological concentrations (0.5-2 microM) As2O3 selectively inhibits growth and causes apoptosis in the megakaryocytic leukemia cell lines HEL, Meg-01, UT7 and M07e. Pertinently, these concentrations of As2O3 resulted in identical changes in the characteristics of the APL cell line NB4, suggesting that As2O3 could produce its effects in both cellular lineages via a common mechanism of action. Various mechanisms have been proposed for the As2O3-induced changes in NB4 (including modulation of promyelocytic leukemia proteins (PML) and Bcl-2, modification of the glutathione redox system, caspase activation, and cell cycle arrest) and are currently under investigation in the megakaryocytic leukemia cell lines. Recent preliminary results indicate that As2O3 downregulates Bcl-2 expression and induces cell cycle arrest in megakaryocytic cell lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders also has been considered. The in vitro effects of As2O3 on a chronic megakaryocytic proliferative disorder. i.e., Essential Thrombocythemia (ET), have been analyzed and megakaryocyte progenitors have shown an unexpectedly higher resistance to As2O3, in comparison to normal megakaryocyte colony-forming cells. The effects of As2O3 on ET and other megakaryocytic disorders need to be fully examined, in order to determine the clinical efficacy of As2O3 in the treatment of syndromes affecting the megakaryocytic lineage.
三氧化二砷（As2O3）已被证明对治疗急性早幼粒细胞白血病（APL）有效，并能抑制APL细胞系NB4的增殖并诱导其凋亡。这种新使用的化疗药物对其他谱系的影响目前正在研究中，以评估其治疗其他人类恶性肿瘤和骨髓增殖综合征的疗效。最近一项研究描述了As2O3对四种不同巨核细胞白血病细胞系的活力、增殖和凋亡诱导的影响。在药理浓度（0.5 - 2 microM）下，As2O3选择性抑制巨核细胞白血病细胞系HEL、Meg - 01、UT7和M07e的生长并导致其凋亡。相关的是，这些浓度的As2O3在APL细胞系NB4中导致了相同的特征变化，表明As2O3可能通过共同的作用机制在两种细胞谱系中产生作用。对于As2O3诱导NB4变化的机制（包括早幼粒细胞白血病蛋白（PML）和Bcl - 2的调节、谷胱甘肽氧化还原系统的修饰、半胱天冬酶激活和细胞周期停滞）已经提出了各种机制，目前正在巨核细胞白血病细胞系中进行研究。最近的初步结果表明，As2O3下调巨核细胞系中Bcl - 2的表达并诱导细胞周期停滞。也有人考虑使用As2O3治疗恶性巨核细胞疾病。已经分析了As2O3对慢性巨核细胞增殖性疾病，即原发性血小板增多症（ET）的体外影响，与正常巨核细胞集落形成细胞相比，巨核细胞祖细胞对As2O3表现出出乎意料的更高抗性。为了确定As2O3在治疗影响巨核细胞谱系的综合征中的临床疗效，需要全面研究As2O3对ET和其他巨核细胞疾病的影响。
