Antivascular actions of microtubule-binding drugs.
Antivascular actions of microtubule-binding drugs.
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DOI：
10.1158/1078-0432.ccr-08-2710
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发表时间：
2009-04-15
期刊：
影响因子：
--
通讯作者：
Schwartz EL
中科院分区：
文献类型：
--
作者：
Schwartz EL
微管结合药物（MBD）广泛用于癌症化疗，也具有临床相关的抗血管生成和血管破坏特性。这些抗血管作用部分是由于对内皮细胞的直接作用，并且所有MBD（即微管稳定和微管不稳定两者）在体外抑制内皮细胞增殖、迁移和管形成，这些作用被认为对应于治疗性抗血管生成作用。此外，微管去稳定剂引起内皮细胞形态的显著变化，这是与体内快速血管塌陷相关的作用。对内皮细胞的影响发生在体外低药物浓度下，其不影响微管总体形态，不引起微管成束或微管损失，并且不诱导细胞周期停滞、细胞凋亡或细胞死亡。相反，已经假设在低浓度下，MBD对微管动力学产生更微妙的影响，阻断关键的细胞信号传导途径，并防止微管与瞬时亚细胞组装体（粘着斑和粘附连接）适当地相互作用，其随后的稳定和/或成熟是细胞运动和细胞-细胞相互作用所需的。本文将重点介绍最近的研究，以确定微管结合药物的抗血管作用的分子机制，这些信息可能是有用的，在识别或设计的代理，其行动更有选择性地针对肿瘤血管。
Microtubule-binding drugs (MBDs) are widely used in cancer chemotherapy and also have clinically relevant anti-angiogenic and vascular-disrupting properties. These anti-vascular actions are due in part to direct effects on endothelial cells, and all MBDs (i.e. both microtubule-stabilizing and -destabilizing) inhibit endothelial cell proliferation, migration, and tube formation in vitro, actions which are thought to correspond to therapeutic anti-angiogenic actions. In addition, the microtubule destabilizing agents cause prominent changes in endothelial cell morphology, an action associated with rapid vascular collapse in vivo. The effects on endothelial cells occur in vitro at low drug concentrations which do not affect microtubule gross morphology, do not cause microtubule bundling or microtubule loss, and do not induce cell cycle arrest, apoptosis, or cell death. Rather it has been hypothesized that at low concentrations, MBDs produce more subtle effects on microtubule dynamics, block critical cell signaling pathways, and prevent the microtubules from properly interacting with transient sub-cellular assemblies (focal adhesions and adherens junctions) whose subsequent stabilization and/or maturation are required for cell motility and cell-cell interactions. This review will focus on recent studies to define the molecular mechanisms for the anti-vascular actions of the microtubule-binding drugs, information which could be useful in the identification or design of agents whose actions more selectively target the tumor vasculature.