Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale
Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale
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DOI：
10.1158/1078-0432.ccr-11-0999
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发表时间：
2012-01-01
影响因子：
11.5
通讯作者：
Fojo, Antonio Tito
中科院分区：
文献类型：
--
作者：
Komlodi-Pasztor, Edina;Sackett, Dan L.;Fojo, Antonio Tito
虽然他们一直提倡与一个可以理解的热情，有丝分裂特异性药物，如有丝分裂激酶和驱动蛋白纺锤体蛋白抑制剂还没有成功的临床。这些药物是在微管靶向药物的成功基础上开发的，同时避免了紫杉烷和长春花生物碱等药物的神经毒性。使用有丝分裂特异性药物的基本原理是基于微管靶向药物的临床疗效可归因于诱导有丝分裂阻滞的论点。然而，后一个概念，这已被长期接受的教条，可能是重要的，只有在细胞培养和快速增长的临床前模型，并在患者肿瘤无关，其中干扰细胞内运输的微管可能是主要的作用机制。在这里，我们回顾了针对有丝分裂的不同抑制剂组的临床前和临床数据，并确定了这些高度特异性的骨髓抑制化合物未能实现其承诺的原因。临床癌症研究; 18（1）; 51-63。(C)2012年AACR。
Although they have been advocated with an understandable enthusiasm, mitosis-specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosis-specific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise. Clin Cancer Res; 18(1); 51-63. (C) 2012 AACR.