Singal Rakesh, Ramachandran Kavitha, Gordian Edna, Quintero Carlos, Zhao Wei, Reis Isildinha M
University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL.
Clin Genitourin Cancer. 2015 Feb;13(1):22-31. doi: 10.1016/j.clgc.2014.07.008. Epub 2014 Aug 1.
Methylation-mediated silencing of genes contributes to docetaxel resistance in prostate cancer. We propose that azacitidine, a demethylating agent, can reverse docetaxel resistance.
Metastatic castration-resistant prostate cancer (mCRPC) patients, who progressed during or within 6 months of docetaxel chemotherapy, were eligible. Fifteen and 7 patients were treated in phase I and II, respectively. In phase I, azacitidine and docetaxel were alternately escalated in a standard 3 + 3 design. All patients received prednisone 5 mg twice daily continuously. Patients were evaluated for toxicity and efficacy. Growth arrest and DNA damage-inducible alpha (GADD45A) methylation was measured before and after azacitidine treatment in the first cycle in phase I patients.
In phase I, no dose-limiting toxicity was observed. At the highest dose (azacitidine 150 mg/m(2) daily for 5 days followed by docetaxel 75 mg/m(2) on day 6), Grade 4 neutropenia was frequent, but infrequent with growth factor. Six patients in the phase II study received the highest dose including growth factor support. The sixth phase II patient died because of neutropenic sepsis. After data and safety monitoring board review, the phase II dose was reduced to azacitidine 75 mg/m(2) daily for 5 days followed by docetaxel 75 mg/m(2) on day 6 with growth factor support. Prostate-specific antigen response was seen in 10 of 19 evaluable patients and objective response was observed in 3 of 10 evaluable patients. Significant demethylation of GADD45A was observed with azacitidine treatment.
The combination of azacitidine, docetaxel, and prednisone with growth factor support is active in mCRPC patients.
基因的甲基化介导沉默促成了前列腺癌对多西他赛的耐药性。我们提出，脱甲基剂阿扎胞苷可逆转多西他赛耐药性。
多西他赛化疗期间或化疗后6个月内病情进展的转移性去势抵抗性前列腺癌（mCRPC）患者符合条件。分别有15例和7例患者在I期和II期接受治疗。在I期，阿扎胞苷和多西他赛按照标准的3 + 3设计交替递增剂量。所有患者持续每日两次口服5 mg泼尼松。对患者进行毒性和疗效评估。在I期患者的第一个周期阿扎胞苷治疗前后测量生长停滞和DNA损伤诱导α（GADD45A）甲基化。
在I期，未观察到剂量限制性毒性。在最高剂量（阿扎胞苷每日150 mg/m²，连用5天，随后在第6天给予多西他赛75 mg/m²）时，4级中性粒细胞减少常见，但使用生长因子后不常见。II期研究中有6例患者接受了包括生长因子支持的最高剂量。II期的第6例患者因中性粒细胞减少性败血症死亡。经过数据和安全监测委员会审查，II期剂量减至阿扎胞苷每日75 mg/m²，连用5天，随后在第6天给予多西他赛75 mg/m²并给予生长因子支持。19例可评估患者中有10例出现前列腺特异性抗原反应，10例可评估患者中有3例观察到客观反应。阿扎胞苷治疗后观察到GADD45A显著去甲基化。
阿扎胞苷、多西他赛和泼尼松联合生长因子支持在mCRPC患者中具有活性。
