文章：

破坏肿瘤血管

Disrupting tumour blood vessels

原文发布日期：2005-06-01

DOI: 10.1038/nrc1628

类型: Review Article

开放获取: 否

要点：

1. Solid tumours require a functional blood supply for their continued growth, and the established tumour vasculature is therefore an attractive target for therapy. Low-molecular-weight vascular-disrupting agents (VDAs) cause the rapid and selective shutdown of tumour blood flow.
2. The combretastatins and drugs related to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are the two main groups of VDAs that are currently in preclinical and clinical development.
3. In endothelial cells in culture, combretastatin A-4 3-O-phosphate (CA-4-P; the lead combretastatin) and DMXAA cause rapid re-organization of the actin cytoskeleton, mediated by disruption of the tubulin cytoskeleton for CA-4-P but not DMXAA.
4. An increase in vascular permeability is likely to be an important component of the mechanisms that lead to the shutdown of tumour blood flow by both classes of drug.
5. Signalling pathways associated with CA-4-P and their effects on permeability involve the small GTPase RHO and RHO kinase, as well as stress-activated protein kinase 2 (SAPK2).
6. The basis for the susceptibility of the tumour vasculature to the VDAs that are currently in preclinical and clinical development is unclear, although there is evidence that, across different tumour types, increased susceptibility correlates with increased permeability of tumour blood vessels.
7. Factors in the tumour microenvironment are likely to influence the susceptibility of tumour blood vessels to VDAs and this is currently under investigation.
8. Other low-molecular-weight VDAs currently under development include several other natural and synthetic combretastatins, other tubulin-binding agents and inhibitors of junctional proteins.
9. Phase I and II clinical trials have confirmed the tumour selectivity of CA-4-P and DMXAA in the clinical setting. The therapeutic potential of VDAs lies in their combination with conventional and/or other novel cancer treatments; such combinations are currently being tested in clinical trials involving radiotherapy, chemotherapy and radioimmunotherapy.

要点翻译：

1. 实体肿瘤的生长需要功能性血液供应，因此已形成的肿瘤血管系统成为有吸引力的治疗靶点。小分子血管破坏剂（VDAs）能够快速、选择性地阻断肿瘤血流。
2. 考布他汀类及5,6-二甲基呫吨酮-4-乙酸（DMXAA）相关药物是目前处于临床前和临床开发阶段的两大类VDAs。
3. 在培养的内皮细胞中，考布他汀A-4 3-O-磷酸酯（CA-4-P；先导考布他汀）和DMXAA均能通过介导肌动蛋白细胞骨架重组快速发挥作用——CA-4-P通过破坏微管蛋白细胞骨架实现此效应，而DMXAA则不依赖此途径。
4. 血管通透性增加可能是这两类药物导致肿瘤血流阻断的重要机制之一。
5. 与CA-4-P相关的信号通路及其对通透性的影响涉及小GTP酶RHO、RHO激酶以及应激激活蛋白激酶2（SAPK2）。
6. 目前尚不清楚肿瘤血管系统对处于临床前和临床开发阶段VDAs易感性的基础，但有证据表明在不同肿瘤类型中，易感性增加与肿瘤血管通透性增强相关。
7. 肿瘤微环境中的因素可能影响肿瘤血管对VDAs的敏感性，这方面研究正在进行中。
8. 其他正在开发的小分子VDAs包括多种天然和合成考布他汀、其他微管结合剂及连接蛋白抑制剂。
9. I期和II期临床试验已证实CA-4-P与DMXAA在临床环境中的肿瘤选择性。VDAs的治疗潜力在于其与传统癌症治疗和/或其他新型疗法的联合应用，目前正在开展的临床试验包括与放疗、化疗及放射免疫治疗的联合方案。

英文摘要：

Low-molecular-weight vascular-disrupting agents (VDAs) cause a pronounced shutdown in blood flow to solid tumours, resulting in extensive tumour-cell necrosis, while they leave the blood flow in normal tissues relatively intact. The largest group of VDAs is the tubulin-binding combretastatins, several of which are now being tested in clinical trials. DMXAA (5,6-dimethylxanthenone-4-acetic acid) — one of a structurally distinct group of drugs — is also being tested in clinical trials. A full understanding of the action of these and other VDAs will provide insights into mechanisms that control tumour blood flow and will be the basis for the development of new therapeutic drugs for targeting the established tumour vasculature for therapy.

摘要翻译： 

低分子量血管破坏剂（VDAs）可显著阻断实体瘤的血流，导致广泛的肿瘤细胞坏死，而对正常组织的血流影响较小。最大的VDA类别是结合微管蛋白的康普立停类，其中多种药物正在进行临床试验。DMXAA（5,6-二甲基呫吨酮-4-乙酸）属于结构不同的药物类别，也在临床试验中。全面理解这些及其他VDAs的作用机制，将有助于揭示调控肿瘤血流的机制，并为开发针对已建立肿瘤血管系统的新型治疗药物奠定基础。

原文链接：

Disrupting tumour blood vessels