The design of selective and non-selective combination therapy for acute promyelocytic leukemia.
The design of selective and non-selective combination therapy for acute promyelocytic leukemia.
复制标题
急性早幼粒细胞白血病选择性和非选择性联合治疗的设计。
DOI：
10.1007/978-3-540-34594-7_13
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发表时间：
2007
影响因子：
--
通讯作者：
Waxman,S
中科院分区：
文献类型：
--
作者：
Jing,Y;Waxman,S
急性早幼粒细胞白血病（APL）是一种独特的急性髓细胞白血病亚型，通常携带特定的相互染色体易位t（15;17），导致白血病生成融合蛋白PML-RARα的表达。APL患者对APL选择性试剂如全反式维甲酸（ATRA）或三氧化二砷和非选择性细胞毒性化疗有反应。几乎所有的初治APL患者在接受ATRA联合化疗或选择性联合治疗（ATRA + As 2 O3）时均获得临床缓解。联合ATRA与As 2 O3作为诱导，随后进行化疗巩固治疗，与单独使用任何药物或任何其他可能的组合治疗相比，可获得更深刻的临床缓解。这些药物的作用机制各不相同。ATRA诱导APL细胞分化及PML-RARα蛋白水解As 2 O3诱导APL细胞部分分化、PML-RARα蛋白水解和凋亡。化疗，主要是使用蒽环类药物，诱导APL细胞死亡。选择性APL治疗（ATRA和As_2O_3）和/或非选择性化疗在APL细胞在体外的联合作用及其与临床方案设计有关的机制进行了讨论。
Acute promyelocytic leukemia (APL) is an unique subtype of acute myeloid leukemia typically carrying a specific reciprocal chromosome translocation, t(15;17), leading to the expression of a leukemia-generating fusion protein, PML-RARα. APL patients are responsive to APL-selective reagents such as all-transretinoic acid (ATRA) or arsenic trioxide and non-selective cytotoxic chemotherapy. Nearly all de novo APL patients undergo clinical remission when treated with ATRA plus chemotherapy or with the combinational selective therapy, ATRA plus As2O3. Combining ATRA with As2O3as an induction followed by chemotherapy consolidation results in more profound clinical remissions compared to treatment with any agent alone or any of the other possible combinations. The mechanism of action of each of these agents differs. ATRA induces APL cell differentiation and PML-RARα proteolysis. As2O3induces APL cell partial differentiation, PML-RARα proteolysis, and apoptosis. Chemotherapy, mainly using anthracyclines, induces APL cell death. The combined effects of selective APL therapy (ATRA and As2O3) and/or non-selective chemotherapy in APL cells in vitro and their mechanisms in relation to clinical protocol design are discussed.