Differentiation therapy of acute myeloid leukemia.
Differentiation therapy of acute myeloid leukemia.
复制标题
DOI：
10.3390/cancers3022402
复制
发表时间：
2011-05-16
期刊：
影响因子：
5.2
通讯作者：
Marcinkowska E
中科院分区：
文献类型：
--
作者：
Gocek E;Marcinkowska E
急性髓性白血病（AML）是成人中的主要急性白血病，其特征在于恶性转化的未成熟髓样前体细胞的积聚。一种非常有吸引力的治疗髓性白血病的方法，现在被称为“分化疗法”，被提出来，因为体外研究表明，多种药物刺激从白血病患者分离的细胞系的分化。分化诱导剂之一全反式维甲酸（all-transretinoic acid，ATRA）可以诱导髓性白血病细胞系中的粒细胞分化，已经被引入临床以治疗患有急性早幼粒细胞白血病（APL）的患者，其中PML-RARA融合蛋白是由t（15;17）（q22;q12）染色体易位产生的。由于分化治疗使用全反式维甲酸显着改善APL患者的预后，许多努力已经找到替代分化剂。由于1，25-二羟维生素D3（1，25 D）能够诱导骨髓性白血病细胞的体外单核细胞/巨噬细胞分化，因此已经进行了临床试验以评估其治疗AML或骨髓增生异常综合征（MDS）患者的潜力。不幸的是，治疗浓度的1，25 D可诱导潜在致命的全身性高钙血症，从而限制了该化合物的临床应用。克服该问题的尝试集中于1，25 D类似物（VDA）的合成，其保留分化诱导潜力，但缺乏其高钙作用。本文就AML的分化治疗中存在的问题及可能的解决方法进行综述。
Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that a variety of agents stimulate differentiation of the cell lines isolated from leukemic patients. One of the differentiation-inducing agents, all-trans retinoic acid (ATRA), which can induce granulocytic differentiation in myeloid leukemic cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a t(15;17)(q22;q12) chromosomal translocation. Because differentiation therapy using ATRA has significantly improved prognosis for patients with APL, many efforts have been made to find alternative differentiating agents. Since 1,25-dihydroxyvitamin D3 (1,25D) is capable of inducing in vitro monocyte/macrophage differentiation of myeloid leukemic cells, clinical trials have been performed to estimate its potential to treat patients with AML or myelodysplastic syndrome (MDS). Unfortunately therapeutic concentrations of 1,25D can induce potentially fatal systemic hypercalcemia, thus limiting clinical utility of that compound. Attempts to overcome this problem have focused on the synthesis of 1,25D analogs (VDAs) which retain differentiation inducing potential, but lack its hypercalcemic effects. This review aims to discuss current problems and potential solutions in differentiation therapy of AML.