The AMD3100 story: The path to the discovery of a stem cell mobilizer (Mozobil)
The AMD3100 story: The path to the discovery of a stem cell mobilizer (Mozobil)
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DOI：
10.1016/j.bcp.2008.12.014
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发表时间：
2009-06-01
影响因子：
5.8
通讯作者：
De Clercq, Erik
中科院分区：
文献类型：
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作者：
De Clercq, Erik
发现AMD 3100在1-10 nM浓度范围内抑制HIV-1和HIV-2，而在高达500 μ M的浓度下对宿主细胞无毒性，从而实现约100，000的选择性指数。最初认为作用靶点是病毒包膜糖蛋白gp 120。它似乎只是间接目标。直接的作用靶点原来是嗜T淋巴细胞的HIV毒株（现在称为X4毒株）进入细胞所使用的辅助受体CXCR 4。作为开发用于治疗艾滋病的候选抗HIV药物的前奏，对AMD 3100进行的初始（I期）临床试验显示了意想不到的副作用：白色血细胞计数增加。显然，AMD 3100特异性增加外周血中的CD 34+造血干细胞计数。基质衍生因子1（SDF-1）通过与CXCR 4相互作用，将干细胞保留在骨髓中（称为“归巢”的过程），而AMD 3100特异性拮抗这种相互作用。AMD 3100与粒细胞集落刺激因子（G-CSF）联合使用比单独使用G-CSF收集更多的祖细胞。目前，AMD 3100（Mozobil（TM））临床使用的主要适应症是将骨髓中的造血干细胞动员到循环血液中，用于非霍奇金淋巴瘤或多发性骨髓瘤等血液恶性肿瘤患者的移植。(c)2008年爱思唯尔公司All rights reserved.
AMD3100 was found to inhibit HIV-1 and HIV-2 within the 1-10 nM concentration range while not being toxic to the host cells at concentrations up to 500 mu M, thus achieving a selectivity index of approximately 100,000. The target of action was initially thought to be the viral envelope glycoprotein gp120. It appeared only to be the indirect target. The direct target of action turned out to be the co-receptor CXCR4 used by T-lymphotropic HIV strains (now referred to as X4 strains) to enter the cells. Initial (phase I) clinical trials undertaken with AMD3100, as a prelude to its development as a candidate anti-HIV drug for the treatment of AIDS, showed an unexpected side effect: an increase in the white blood cell counts. Apparently, AMD3100 specifically increased CD34+ hematopoietic stem cell counts in the peripheral blood. Stromal derived factor 1 (SDF-1), through its interaction with CXCR4, retains the stem cells in the bone marrow (a process referred to as "homing"), and AMD3100 specifically antagonizes this interaction. AMD3100 in combination with granulocyte colony-stimulating factor (G-CSF) resulted in the collection of more progenitor cells than G-CSF alone. At present, the major indication for clinical use of AMD3100 (Mozobil (TM)) is the mobilization of hematopoietic stem cells from the bone marrow into the circulating blood for transplantation in patients with hematological malignancies such as non-Hodgkin's lymphoma or multiple myeloma. (c) 2008 Elsevier Inc. All rights reserved.