Division of Cancer Medicine and Blood Diseases, University of Southern California, Los Angeles, California, USA.
Oncologist. 2011;16(10):1349-58. doi: 10.1634/theoncologist.2010-0014. Epub 2011 Sep 30.
The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.
去势抵抗性前列腺癌（CRPC）的治疗存在临床挑战，因为目前可用的治疗方法在疗效和持久性方面存在局限性。埃坡霉素是一类新型的抗癌治疗药物，可稳定微管，在临床前模型中导致细胞死亡和肿瘤消退。埃坡霉素结合微管的结构与紫杉烷类药物不同。此外，临床前研究表明埃坡霉素与紫杉烷类药物之间存在非重叠的耐药机制。在 CRPC 患者的早期研究中，半合成埃坡霉素 B 类似物伊沙匹隆治疗先前接受基于多西紫杉醇方案治疗进展的男性，可诱导客观反应和前列腺特异性抗原下降。在非随机试验中，伊沙匹隆在一线和二线环境中作为单一药物以及与雌莫司汀联合使用，观察到 CRPC 患者具有临床活性。帕他匹隆和沙格匹隆在 CRPC 患者的 II 期临床试验中也显示出有希望的疗效。所有三种埃坡霉素类药物耐受性良好，中性粒细胞减少症和周围神经病的发生率较低。埃坡霉素类药物与紫杉烷类药物之间缺乏交叉耐药性，可能允许这些药物的序贯使用。在 III 期比较试验中评估埃坡霉素类药物将为它们在 CRPC 患者管理中的潜在地位提供急需的见解。
