Pellegrini Federico, Budman Daniel R
Experimental Therapeutics Section, Don Monti Division of Oncology, North Shore University Hospital, New York University School of Medicine, Manhasset, New York 11030, USA.
Cancer Invest. 2005;23(3):264-73. doi: 10.1081/cnv-200055970.
Anticancer agents that interfere with microtubulin function are in widespread use in man and have a broad spectrum of activity against both hematological malignancies and solid tumors. The mechanisms of actions of these agents have been better defined during the past decade, indicating that there are distinct binding sites for these agents and that they interfere with microtubulin dynamics (growth and shortening of tubules) at low concentrations and only evoke microtubulin aggregation or dissociation at high concentrations. Tubulin has been recently described in the nucleus of cells and in mitochondria. Downstream events from tubulin binding are believed to be critical events for the generation of apoptosis in the malignant cell. The effects of vinca alkaloids and taxanes are distinct, suggesting that the interference with the tubulin cap by high-affinity binding of effective agents is not the only mechanism of cytotoxic effect, and the low-affinity binding of drug, which distorts microtubulin function, may also be important. The epothilones share some of the binding characteristics of the taxanes and are in clinical trials because of cytoxic activity in taxane resistant cells. Tubulin has additional target sites for anticancer drugs including interference with the binding and function of microtubule associated proteins and interference with motor proteins which are essential for the transport of substances within the cell. Because many of these microtubule associated proteins have an ATP binding site, both computer-aided design and combinatorial chemistry techniques can be used to make agents to interfere with their function analogous to imatinib mesylate (Gleevec). Agents that interfere with the motor protein kinesin are entering clinical trials.
干扰微管蛋白功能的抗癌药物在临床上广泛应用，对血液系统恶性肿瘤和实体瘤均具有广泛的活性。在过去十年中，这些药物的作用机制已得到更明确的阐释，表明这些药物存在不同的结合位点，它们在低浓度时干扰微管蛋白动力学（微管的生长和缩短），仅在高浓度时引起微管蛋白聚集或解离。最近在细胞核和线粒体中发现了微管蛋白。微管蛋白结合后的下游事件被认为是恶性细胞中诱导凋亡的关键事件。长春花生物碱和紫杉烷的作用效果不同，这表明有效药物的高亲和力结合对微管蛋白帽的干扰并非细胞毒性作用的唯一机制，药物的低亲和力结合导致微管蛋白功能紊乱可能也很重要。埃坡霉素具有一些紫杉烷的结合特性，因其对紫杉烷耐药细胞具有细胞毒性活性而正在进行临床试验。微管蛋白还有其他抗癌药物作用靶点，包括干扰微管相关蛋白的结合和功能以及干扰对细胞内物质运输至关重要的驱动蛋白。由于许多这些微管相关蛋白都有一个ATP结合位点，计算机辅助设计和组合化学技术都可用于制备类似于甲磺酸伊马替尼（格列卫）的干扰其功能的药物。干扰驱动蛋白的药物已进入临床试验阶段。
