Mifepristone Has Limited Activity to Enhance the In Vivo Efficacy of Docetaxel and Enzalutamide Against Bone Metastatic and Castration-Resistant Prostate Cancer.
Mifepristone Has Limited Activity to Enhance the In Vivo Efficacy of Docetaxel and Enzalutamide Against Bone Metastatic and Castration-Resistant Prostate Cancer.
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DOI：
10.21873/anticanres.12074
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发表时间：
2017-11
影响因子：
2
通讯作者：
Yang Yang-Yang;Xin Li;K. Mamouni;O. Kucuk;Daqing Wu
中科院分区：
文献类型：
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作者：
Yang Yang-Yang;Xin Li;K. Mamouni;O. Kucuk;Daqing Wu
米非司酮作为一种治疗人类癌症（包括前列腺癌）的新型药物的潜力引起了人们的极大兴趣。然而，最近在前列腺癌和其他癌症中使用米非司酮的临床试验结果令人失望。我们评估了米非司酮与多西他赛和恩杂鲁胺联合治疗骨转移性去势抵抗性前列腺癌的体内和体外活性。材料与方法采用比色法测定米非司酮单独或与多西他赛或恩杂鲁胺联合使用对体外PCa细胞活力的影响。采用胸腺裸鼠C4-2-Luc肿瘤胫骨内模型，评价米非司酮单用或与多西他赛、恩杂鲁胺联用的体内疗效。通过血清前列腺特异性抗原（PSA）水平和x线摄影评估小鼠骨中的肿瘤生长情况。结果虽然米非司酮与多西他赛或恩杂鲁胺在细胞培养中表现出一定程度的协同作用，但统计分析显示，联合用药在抑制前列腺癌骨骼生长和增强多西他赛或恩杂鲁胺在胸腺裸鼠体内的疗效方面没有效果（p < 0.05）。结论这些结果首次提供了临床前证据，表明米非司酮可能无法有效抑制骨转移性前列腺癌，无论是单独使用还是与标准化疗和雄激素剥夺治疗联合使用。该报告可能引起对米非司酮在晚期PCa治疗中的临床应用的关注。
BACKGROUND Mifepristone has gained great interest in its potential as a novel agent against human cancers, including prostate cancer (PCa). However, recent clinical trials using mifepristone in PCa and other cancers have been disappointing. We evaluated the in vitro and in vivo activities of mifepristone, in combination with docetaxel and enzalutamide, against bone metastatic castration-resistant PCa. MATERIALS AND METHODS The effects of mifepristone, alone or in combination with docetaxel or enzalutamide, on PCa cell viability, in vitro, were determined by the colorimetric assay. Intratibial model of C4-2-Luc tumors in athymic nude mice was used to evaluate the in vivo efficacy of mifepristone alone or in combination with docetaxel or enzalutamide. Tumor growth in mouse bone was assessed by serum prostate-specific antigen (PSA) levels and radiography. RESULTS Although mifepristone exhibits a certain degree of synergism with docetaxel or enzalutamide in cell culture, statistical analyses showed that combination regimens fail to demonstrate effectiveness in suppressing the skeletal growth of PCa and enhancing the in vivo efficacy of docetaxel or enzalutamide in athymic nude mice (p>0.05). CONCLUSION These results provide the first pre-clinical evidence suggesting that mifepristone may not effectively inhibit bone metastatic PCa, either as a single agent or combined with standard chemotherapy and androgen-deprivation therapy. This report may raise concerns over the clinical use of mifepristone in the management of advanced PCa.