文章：

靶向抗有丝分裂治疗：我们能改进微管蛋白药物吗？

Targeted anti-mitotic therapies: can we improve on tubulin agents?

原文发布日期：2007-02-01

DOI: 10.1038/nrc2049

类型: Review Article

开放获取: 否

要点：

1. Anti-mitotic therapies that target tubulin are effective and widely used in treating cancer, but they have limitations related to the role of tubulin in the cytoskeleton of normal cells.
2. New compounds that inhibit new targets with specific functions in mitosis have now been identified, and show promising anti-tumour activity in preclinical model systems.
3. Early clinical studies have begun to show the pharmacodynamic activities of these new compounds in cancer patients.
4. These new mitotic inhibitors are very effective at preventing the proliferation of most tumour cells in vitro, but the subsequent cellular response to cell-cycle arrest is quite varied and includes apoptosis, mitotic catastrophe, mitotic slippage, senescence and reversible mitotic arrest depending on what cell line and/or inhibitor is studied.
5. At present, the genetic or biochemical factors that define how a particular tumour cell will respond to mitotic injuries are poorly understood, but will be very important in helping to identify which patients will be the best candidates for treatment with these new agents.

要点翻译：

1. 以微管蛋白为靶点的抗有丝分裂疗法在癌症治疗中有效且应用广泛，但其疗效受限于微管蛋白在正常细胞骨架中的功能。
2. 目前已有针对有丝分裂过程中特定功能新靶点的化合物被发现，并在临床前模型体系中展现出良好的抗肿瘤活性。
3. 早期临床研究开始揭示这些新化合物在癌症患者体内的药效学活性。
4. 这类新型有丝分裂抑制剂在体外能有效阻止大多数肿瘤细胞增殖，但后续细胞对细胞周期阻滞的反应存在显著差异——根据所研究的细胞系和/或抑制剂类型不同，可呈现细胞凋亡、有丝分裂灾难、有丝分裂滑移、细胞衰老及可逆性有丝分裂阻滞等多种状态。
5. 目前，对于决定特定肿瘤细胞如何应对有丝分裂损伤的遗传或生化因素尚不明确，但这一机制的阐明对筛选最适合接受此类新药治疗的患者群体至关重要。

英文摘要：

The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.

摘要翻译： 

分子靶向药物发现的出现，促进了一类新一代抗有丝分裂疗法的识别，这些疗法针对在有丝分裂中具有特定功能的蛋白质。它们对有丝分裂的精细选择性，以及这些新药物干扰有丝分裂的不同方式，不仅有望克服当前靶向微管蛋白的抗有丝分裂药物的某些局限性，还能扩大这些药物已确立的临床疗效范围。将这些新的抗有丝分裂药物开发为靶向疗法面临重大挑战；然而，这些潜在疗法也作为独特工具，用于剖析有丝分裂检查点反应的分子机制。

原文链接：

Targeted anti-mitotic therapies: can we improve on tubulin agents?