Leukemia regression by vascular disruption and antiangiogenic therapy
Leukemia regression by vascular disruption and antiangiogenic therapy
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DOI：
10.1182/blood-2009-06-230474
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发表时间：
2010-09-02
期刊：
影响因子：
20.3
通讯作者：
Cogle, Christopher R.
中科院分区：
文献类型：
--
作者：
Madlambayan, Gerard J.;Meacham, Amy M.;Cogle, Christopher R.
急性髓性白血病（AML）和内皮细胞的生存和增殖相互依赖。单药抗血管策略，如靶向血管内皮生长因子（VEGF）治疗AML的疗效有限。因此，为了寻找AML的多靶点抗血管治疗策略，我们测试了一种新的血管破坏剂OXi 4503，单独使用和与抗VEGF抗体贝伐单抗联合使用。使用异种移植动物模型，OXi 4503治疗人AML绿色瘤导致白血病核心中的血管破坏，其显示增加的白血病细胞凋亡。然而，白血病细胞的存活边缘仍然存在，并且血管丰富，VEGF-A表达增加。为了靶向这种外周反应性血管生成，将贝伐单抗与OXi 4503组合并消除有活力的血管边缘，从而导致增强的白血病消退。在原发性人AML的系统性模型中，OXi 4503单独和与贝伐单抗组合使白血病植入消退。单独的血管密度差异不能解释所观察到的消退，表明OXi 4503还表现出对白血病细胞的直接细胞毒性作用。体外分析证实了这种靶向效应，其由活性氧的产生介导并导致细胞凋亡。总之，这些数据表明单独的OXi 4503能够通过多靶向机制使AML消退，并且贝伐单抗的添加减轻了反应性血管生成。（血。2010;116（9）：1539-1547）
Acute myelogenous leukemias (AMLs) and endothelial cells depend on each other for survival and proliferation. Monotherapy antivascular strategies such as targeting vascular endothelial growth factor (VEGF) has limited efficacy in treating AML. Thus, in search of a multitarget antivascular treatment strategy for AML, we tested a novel vascular disrupting agent, OXi4503, alone and in combination with the anti-VEGF antibody, bevacizumab. Using xenotransplant animal models, OXi4503 treatment of human AML chloromas led to vascular disruption in leukemia cores that displayed increased leukemia cell apoptosis. However, viable rims of leukemia cells remained and were richly vascular with increased VEGF-A expression. To target this peripheral reactive angiogenesis, bevacizumab was combined with OXi4503 and abrogated viable vascular rims, thereby leading to enhanced leukemia regression. In a systemic model of primary human AML, OXi4503 regressed leukemia engraftment alone and in combination with bevacizumab. Differences in blood vessel density alone could not account for the ob-served regression, suggesting that OXi4503 also exhibited direct cytotoxic effects on leukemia cells. In vitro analyses confirmed this targeted effect, which was mediated by the production of reactive oxygen species and resulted in apoptosis. Together, these data show that OXi4503 alone is capable of regressing AML by a multitargeted mechanism and that the addition of bevacizumab mitigates reactive angiogenesis. (Blood. 2010;116(9):1539-1547)