文章：

微管作为抗癌药物的靶标

Microtubules as a target for anticancer drugs

原文发布日期：2004-04-01

DOI: 10.1038/nrc1317

类型: Review Article

开放获取: 否

要点：

1. Microtubules are highly dynamic cytoskeletal fibres that are composed of tubulin subunits. They show two types of non-equilibrium dynamics — treadmilling and dynamic instability — both of which are crucial to mitosis and cell division.
2. Dynamic microtubules continue to be one of the most successful cancer chemotherapeutic targets. Many new drugs that target microtubules are in clinical trials and large numbers of microtubule-active compounds are being developed.
3. Among the most successful microtubule-targeted chemotherapeutic drugs are paclitaxel and the Vinca alkaloids, which were previously thought to work through opposite mechanisms. We now recognize that their most potent actions are suppression of microtubule dynamics, rather than increasing or decreasing microtubule-polymer mass.
4. Microtubule-active drugs generally bind to one of three main classes of sites on tubulin, the paclitaxel site, the Vinca domain and the colchicine domain. Drugs that bind to the colchicine domain are undergoing intensive investigation as vascular-targeting agents for cancer therapy.
5. Development of resistance to microtubule-targeted drugs has several possible causes, some of which might involve changes in microtubule dynamics resulting from altered expression of tubulin isotypes, tubulin mutations, and altered expression or binding of microtubule-regulatory proteins.
6. Microtubule-targeted drugs can synergize with one another.
7. Understanding their modes of action might lead to improved dosing regimens and combinations with other microtubule-targeted drugs, as well as combinations with 'molecularly targeted' drugs.

要点翻译：

1. 微管是由微管蛋白亚基构成的高度动态的细胞骨架纤维。它们表现出两种非平衡动力学——踏车行为和动态不稳定性——这两者对于有丝分裂和细胞分裂都至关重要。
2. 动态微管始终是最成功的癌症化疗靶点之一。许多靶向微管的新药正处于临床试验阶段，大量具有微管活性的化合物正在研发中。
3. 最成功的微管靶向化疗药物包括紫杉醇和长春花生物碱，这些药物曾被认为通过相反机制发挥作用。我们现在认识到，它们最有效的作用是抑制微管动力学，而非增加或减少微管聚合物质量。
4. 微管活性药物通常结合于微管蛋白上的三类主要位点之一：紫杉醇结合位点、长春碱结构域和秋水仙碱结构域。与秋水仙碱结构域结合的药物作为癌症治疗的血管靶向剂正在接受深入研究。
5. 对微管靶向药物产生耐药性的发展有多种可能原因，其中一些可能涉及微管蛋白亚型表达改变、微管蛋白突变、以及微管调节蛋白表达或结合变化所导致的微管动力学改变。
6. 微管靶向药物彼此之间可产生协同作用。
7. 理解其作用机制可能有助于改进给药方案、优化与其他微管靶向药物的组合应用，以及推动与"分子靶向"药物的联合治疗。

英文摘要：

Highly dynamic mitotic-spindle microtubules are among the most successful targets for anticancer therapy. Microtubule-targeted drugs, including paclitaxel and Vinca alkaloids, were previously considered to work primarily by increasing or decreasing the cellular microtubule mass. Although these effects might have a role in their chemotherapeutic actions, we now know that at lower concentrations, microtubule-targeted drugs can suppress microtubule dynamics without changing microtubule mass; this action leads to mitotic block and apoptosis. In addition to the expanding array of chemically diverse antimitotic agents, some microtubule-targeted drugs can act as vascular-targeting agents, rapidly depolymerizing microtubules of newly formed vasculature to shut down the blood supply to tumours.

摘要翻译： 

高度动态的有丝分裂纺锤体微管是抗癌治疗中最成功的靶点之一。包括紫杉醇和长春花生物碱在内的微管靶向药物，曾被认为主要通过增加或减少细胞内微管总量发挥作用。尽管这些效应可能在其化疗作用中扮演一定角色，但我们现在知道，在较低浓度下，微管靶向药物可在不改变微管总量的情况下抑制微管动力学；这一作用可导致有丝分裂阻滞和细胞凋亡。除了不断扩展的化学结构多样的抗有丝分裂药物外，某些微管靶向药物还可作为血管靶向药物，迅速使新生血管的微管解聚，从而切断肿瘤的血液供应。

原文链接：

Microtubules as a target for anticancer drugs