BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy
BNC105: A Novel Tubulin Polymerization Inhibitor That Selectively Disrupts Tumor Vasculature and Displays Single-Agent Antitumor Efficacy
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DOI：
10.1158/1535-7163.mct-09-0815
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发表时间：
2010-06-01
影响因子：
5.7
通讯作者：
Flynn, Bernard
中科院分区：
文献类型：
--
作者：
Kremmidiotis, Gabriel;Leske, Annabell F.;Flynn, Bernard
血管阻断剂（VDA）导致肿瘤血管闭塞，导致缺氧驱动的肿瘤细胞坏死。肿瘤血管破坏是一种具有巨大潜力的治疗策略;然而，目前正在开发的VDA显示出狭窄的治疗范围，心血管毒性构成了剂量限制性障碍。发现新的VDA，显示更宽的治疗范围，可能会改善临床结局。为了鉴定这些化合物，我们使用了体外选择性筛选方法，该方法利用了肿瘤内皮细胞处于恒定的活化和血管生成状态并且不经历衰老的事实。我们的努力产生了化合物BNC 105。该化合物作为微管蛋白聚合抑制剂，与稳定毛细血管中发现的非增殖内皮细胞或内皮细胞相比，对活跃增殖或参与体外毛细血管形成的内皮细胞显示出80倍的效力。在CA 4中未观察到这种选择性，CA 4是目前正在III期临床试验中评价的VDA。BNC 105更有效，并提供更宽的治疗窗口。CA 4在其无明显不良事件水平（NOAEL）下产生90%的血管破裂，而BNC 105在其NOAEL的1/8下引起95%的血管破裂。BNC 105在荷瘤小鼠中的组织分布分析显示，尽管药物在给药后24小时从所有组织中清除，但其仍以高浓度存在于实体瘤块中。此外，BNC 105治疗导致肿瘤消退，在20%的治疗动物中完全清除肿瘤。Mol Cancer Ther; 9（6）; 1562-73.（C）2010年AACR。
Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals. Mol Cancer Ther; 9(6); 1562-73. (C)2010 AACR.