Morris Patrick G, Fornier Monica N
Memorial Sloan-Kettering Cancer Center, Breast Cancer Medicine Service, New York, New York 10021, USA.
Clin Cancer Res. 2008 Nov 15;14(22):7167-72. doi: 10.1158/1078-0432.CCR-08-0169.
Microtubules are essential to cell transport, signaling, and mitosis. An increasing range of anticancer drugs interferes with the normal formation and function of microtubules. Vinca alkaloids act as microtubule destabilizers and the taxanes act as microtubule stabilizers. Taxanes are widely used cytotoxic agents that are active in a range of solid tumor malignancies and are routinely used in a variety of settings. Significant limitations with the taxanes exist, including acquired and intrinsic tumor resistance through the expression of multidrug resistance proteins such as P-glycoprotein, risk of hypersensitivity reactions, dose-limiting hematopoietic toxicity, and cumulative neurotoxicity. Hence, there is a need to develop novel agents that act on the microtubules. Epothilones are macrolide antibiotics that bind near the taxane-binding site on microtubules and have been extensively studied in recent and ongoing clinical trials. A variety of other agents that act on the microtubules at different sites with a variety of structures are at varying stages of development.
微管对于细胞运输、信号传导和有丝分裂至关重要。越来越多的抗癌药物会干扰微管的正常形成和功能。长春花生物碱充当微管去稳定剂，紫杉烷类充当微管稳定剂。紫杉烷类是广泛使用的细胞毒性药物，对一系列实体瘤恶性肿瘤具有活性，并常规用于多种情况。紫杉烷类存在显著局限性，包括通过表达多药耐药蛋白（如P-糖蛋白）产生获得性和固有肿瘤耐药性、过敏反应风险、剂量限制性造血毒性以及累积神经毒性。因此，需要开发作用于微管的新型药物。埃坡霉素是大环内酯类抗生素，它们结合在微管上紫杉烷结合位点附近，并且在最近和正在进行的临床试验中得到了广泛研究。其他多种作用于微管不同位点、具有多种结构的药物正处于不同的开发阶段。
