Lee James J, Kelly W Kevin
Section of Medical Oncology, Department of Internal Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Nat Clin Pract Oncol. 2009 Feb;6(2):85-92. doi: 10.1038/ncponc1281. Epub 2008 Dec 2.
Microtubules are vital and dynamic cellular organelles and many agents have been developed that target them. The cytotoxic effects of taxanes and epothilones are mediated by stabilization of microtubule dynamics. Taxanes are one of the most effective cytotoxic agents, and have a broad spectrum of antitumor activity. However, their efficacy is limited by the development of resistance to these effects. Epothilones have a similar mechanism of action to taxanes, but a decreased propensity for drug resistance. Epothilones are macrolides, and have in vitro and in vivo activity in taxane-resistant or taxane-insensitive human cancer cell lines. Several epothilones are in clinical development: ixabepilone, patupilone, BMS-310705, KOS-862, KOS-1584, and ZK-EPO. Multiple dosing schedules of ixabepilone and patupilone have been studied. The toxicity profiles of epothilones are quite diverse and depend on the compound and the administration schedule. The epothilones have demonstrated a wide range of clinical activity, including important antitumor effects, in advanced prostate cancer. Epothilones are particularly useful in patients with prostate cancer who have previously been treated with taxanes or who have taxane-refractory tumors. In the setting of castrate metastatic prostate cancer, ixabepilone and patupilone showed encouraging clinical activity in the phase II setting and further studies are needed to determine if they provide additional clinical benefit to patients with advanced disease.
微管是重要且动态的细胞器，人们已研发出许多靶向微管的药物。紫杉烷类和埃坡霉素的细胞毒性作用是通过稳定微管动力学来介导的。紫杉烷类是最有效的细胞毒性药物之一，具有广泛的抗肿瘤活性。然而，其疗效因对这些作用产生耐药性而受到限制。埃坡霉素的作用机制与紫杉烷类相似，但耐药倾向较低。埃坡霉素是大环内酯类化合物，在紫杉烷耐药或对紫杉烷不敏感的人癌细胞系中具有体外和体内活性。几种埃坡霉素正处于临床开发阶段：伊沙匹隆、帕妥匹隆、BMS-310705、KOS-862、KOS-1584和ZK-EPO。已对伊沙匹隆和帕妥匹隆的多种给药方案进行了研究。埃坡霉素的毒性特征差异很大，取决于化合物和给药方案。埃坡霉素在晚期前列腺癌中已显示出广泛的临床活性，包括重要的抗肿瘤作用。埃坡霉素对先前接受过紫杉烷类治疗或患有紫杉烷难治性肿瘤的前列腺癌患者特别有用。在去势转移性前列腺癌的情况下，伊沙匹隆和帕妥匹隆在II期试验中显示出令人鼓舞的临床活性，需要进一步研究以确定它们是否能为晚期疾病患者提供额外的临床益处。
