Strategy for the treatment of acute myelogenous leukemia based on folate receptor β-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid
Strategy for the treatment of acute myelogenous leukemia based on folate receptor β-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid
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DOI：
10.1182/blood.v100.2.594
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发表时间：
2002-07-15
期刊：
影响因子：
20.3
通讯作者：
Lee, RJ
中科院分区：
文献类型：
--
作者：
Pan, XQ;Zheng, X;Lee, RJ
全反式维甲酸(ATRA)上调急性髓系白血病(AML)患者叶酸受体(FR)-β的表达，并限制其正常组织分布，使其成为潜在的治疗靶点。外周血粒细胞中的FR-β不能结合叶酸，并且似乎有一个变异的GPI膜锚，这从它对磷脂酰肌醇特异性磷脂酶C不敏感而对亚硝酸不敏感可见一斑。粒细胞FR-β缺乏突变，去糖基化和洗涤剂增溶都不能恢复叶酸结合。从78例不同亚型AML骨髓标本的流式细胞术分析中发现，与叶酸结合的AML细胞的FR-β明显缺乏翻译后修饰导致其功能丧失，其中68%表达FR-β，其中大部分也是CD34(+)。在FR(-)(KG-1a、L1210和中国仓鼠卵巢[CHO])或FR(+)(KG-1、L1210 JF和重组CHO-FR-β)模型细胞系中，分别包裹荧光钙黄绿素(f-L-钙黄绿素)和阿霉素(f-L-DOX)的叶酸包裹脂质体可以被1 mM的游离叶酸阻断，获得选择性的FR结合和细胞毒作用。在表达FR-beta的KG-1人AML细胞中，全反式维甲酸处理进一步增强了这种特异性。在用L1210JF或KG-1细胞建立的小鼠腹水性白血病模型中，f-L-DOX治疗组与非靶向L-DOX治疗组相比，中位生存期延长。在KG-1模型中，全反式维甲酸治疗将f-L-DOX的治愈率从10%提高到60%。以上来自我们两个实验室的综合数据进一步支持了选择性全反式维甲酸促进的脂质体在FR-beta(+)AML中应用的可行性和潜在的有效性。(C)2002年，由美国血液病学会公布。
Up-regulation of folate receptor (FR) type-beta in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and Its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-beta in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its Insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-beta lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evidently absent In FR-beta from AML cells from patient marrow, which bound folate, From flow cytometric analysis of 78 AML bone marrow specimens of different sub-types, 68% expressed FR-beta, most of which were also CD34(+). In model cell lines that are FR (-) (KG-1a, L1210, and Chinese hamster ovary [CHO]) or FR (+) (KG-1, L1210 JF, and recombinant CHO-FR-beta), selective FR-mediated binding and cytotoxicity was obtained using folate-coated liposomes encapsulating fluorescent calcein (f-L-calcein) and doxorubicin (f-L-DOX), respectively, which could be blocked by 1 mM free folic acid. In the FR-beta-expressing KG-1 human AML cells, treatment with ATRA further Increased this specificity. In mouse ascites leukemia models generated using L1210JF or KG-1 cells, Increased median survival times were obtained with f-L-DOX treatment compared to nontargeted L-DOX. In the KG-1 model, ATRA treatment Increased the cure rate with f-L-DOX from 10% to 60%. The above combined data from our 2 laboratories further support the feasibility and potential usefulness of selective ATRA-facilitated liposomal drug delivery In FR-beta (+) AMLs. (C) 2002 by The American Society of Hematology.