Targeting androgen receptor(AR)has shown great therapeutic potential in triple-negative breast cancer(TNBC),yet its efficacy remains unsatisfactory.Here,we aimed to identify promising targeted agents that synergize wi...Targeting androgen receptor(AR)has shown great therapeutic potential in triple-negative breast cancer(TNBC),yet its efficacy remains unsatisfactory.Here,we aimed to identify promising targeted agents that synergize with enzalutamide,a second-generation AR inhibitor,in TNBC.By using a strategy for screening drug combinations based on the Sensitivity Index(SI),we found that MK-8776,a selective checkpoint kinase1(CHK1)inhibitor,showed favorable synergism with enzalutamide in AR-positive TNBC.The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776,respectively.Furthermore,a nanoparticle-based on hyaluronic acid(HA)-modified hollow-manganese dioxide(HMnO_(2)),named HMnE&M@H,was established to encapsulate and deliver enzalutamide and MK-8776.This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness.HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier.Collectively,our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H,providing a potential therapeutic approach for the treatment of TNBC.展开更多
This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate （AA） and enzalutamide （Enz） for metastatic castration-resistant prostate cancer （mCRPC）. A lit...This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate （AA） and enzalutamide （Enz） for metastatic castration-resistant prostate cancer （mCRPC）. A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA （active comparator） and Enz （true placebo） randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings （HR. 0.90, 95% CI, 0.73-1.11; HR： 0.85, 95% CI, 0.68-1.07）. Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons： time to prostate-specific antigen （PSA） progression （HR. 0.34, 95% CI, 0.28-0.42; HR： 0.40, 95% CI, 0.30-0.53）, radiographic progression-free survival （HR： 0.37, 95% CI, 0.28-0.48; HR： 0.61, 95% CI, 0.50-0.74）, and PSA response rate （OR： 18.29, 95% CI, 11.20-29.88; OR： 10.69, 95% CI, 3.92-29.20）. With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.展开更多
目的:快速评估恩扎卢胺(ENZ)治疗前列腺癌的有效性、安全性和经济性,为临床合理用药和决策者提供参考。方法:计算机检索PubMed、Web of Science、Cochrane Library、Scopus、Embase、EBSCO、CNKI、Wanfang Data、VIP、CBM数据库和国内...目的:快速评估恩扎卢胺(ENZ)治疗前列腺癌的有效性、安全性和经济性,为临床合理用药和决策者提供参考。方法:计算机检索PubMed、Web of Science、Cochrane Library、Scopus、Embase、EBSCO、CNKI、Wanfang Data、VIP、CBM数据库和国内外卫生技术评估(HTA)相关网站,纳入ENZ相关的HTA报告、系统综述/Meta分析和经济学评价。由2位研究员依据纳入排除标准筛选文献、数据提取和质量评价,并对结果进行定性分析。结果:共纳入51篇文献,包含4篇HTA报告,36篇系统综述/Meta分析和11篇经济学评价。有效性和安全性方面,对于非转移性去势抵抗性前列腺癌(nmCRPC),与安慰剂或达罗他胺相比,ENZ可显著延长无进展生存期(PFS)和无转移生存期(MFS);与安慰剂相比,显著增加不良事件的发生风险。对于转移性去势抵抗性前列腺癌(mCRPC),与安慰剂、阿比特龙、卡巴他赛和Sipuleucel-T相比,ENZ可显著延长PFS;与安慰剂相比,显著增加高血压和疲劳的发生风险。对于转移性激素敏感性前列腺癌(mHSPC),与雄激素剥夺治疗(ADT)、多西他赛联合ADT相比,ENZ联合ADT可显著延长PFS和OS。经济性方面,与阿比特龙相比,ENZ治疗化疗初治或内脏mCRPC患者具有成本-效果优势。结论:ENZ治疗前列腺癌具有良好的有效性和安全性,经济性有待进一步研究。展开更多
An improved and practical synthesis of enzalutamide was accomplished in five steps.Starting from 4-bromo-2-fluoro-benzonic acid,a methyl esterification,Ullmann ligation,methyl esterification,ring closing reaction and ...An improved and practical synthesis of enzalutamide was accomplished in five steps.Starting from 4-bromo-2-fluoro-benzonic acid,a methyl esterification,Ullmann ligation,methyl esterification,ring closing reaction and final methyl amidation provided the target in 35% total yield with 99.8% purity.Five identified impurities were also synthesized.This efficient and economical procedure avoids the use of highly toxic reagents and multiple recrystallization operations,which is suitable for further industrialization.展开更多
基金supported by the Key INTERNATIONAL COOPERATION of the National Natural Science Foundation of China(No.81920108029,China)the Key Foundation for Social Development Project of the Jiangsu Province,China(No.BE2021741,China).
文摘Targeting androgen receptor(AR)has shown great therapeutic potential in triple-negative breast cancer(TNBC),yet its efficacy remains unsatisfactory.Here,we aimed to identify promising targeted agents that synergize with enzalutamide,a second-generation AR inhibitor,in TNBC.By using a strategy for screening drug combinations based on the Sensitivity Index(SI),we found that MK-8776,a selective checkpoint kinase1(CHK1)inhibitor,showed favorable synergism with enzalutamide in AR-positive TNBC.The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776,respectively.Furthermore,a nanoparticle-based on hyaluronic acid(HA)-modified hollow-manganese dioxide(HMnO_(2)),named HMnE&M@H,was established to encapsulate and deliver enzalutamide and MK-8776.This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness.HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier.Collectively,our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H,providing a potential therapeutic approach for the treatment of TNBC.
文摘This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate （AA） and enzalutamide （Enz） for metastatic castration-resistant prostate cancer （mCRPC）. A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA （active comparator） and Enz （true placebo） randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings （HR. 0.90, 95% CI, 0.73-1.11; HR： 0.85, 95% CI, 0.68-1.07）. Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons： time to prostate-specific antigen （PSA） progression （HR. 0.34, 95% CI, 0.28-0.42; HR： 0.40, 95% CI, 0.30-0.53）, radiographic progression-free survival （HR： 0.37, 95% CI, 0.28-0.48; HR： 0.61, 95% CI, 0.50-0.74）, and PSA response rate （OR： 18.29, 95% CI, 11.20-29.88; OR： 10.69, 95% CI, 3.92-29.20）. With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.
文摘目的:快速评估恩扎卢胺(ENZ)治疗前列腺癌的有效性、安全性和经济性,为临床合理用药和决策者提供参考。方法:计算机检索PubMed、Web of Science、Cochrane Library、Scopus、Embase、EBSCO、CNKI、Wanfang Data、VIP、CBM数据库和国内外卫生技术评估(HTA)相关网站,纳入ENZ相关的HTA报告、系统综述/Meta分析和经济学评价。由2位研究员依据纳入排除标准筛选文献、数据提取和质量评价,并对结果进行定性分析。结果:共纳入51篇文献,包含4篇HTA报告,36篇系统综述/Meta分析和11篇经济学评价。有效性和安全性方面,对于非转移性去势抵抗性前列腺癌(nmCRPC),与安慰剂或达罗他胺相比,ENZ可显著延长无进展生存期(PFS)和无转移生存期(MFS);与安慰剂相比,显著增加不良事件的发生风险。对于转移性去势抵抗性前列腺癌(mCRPC),与安慰剂、阿比特龙、卡巴他赛和Sipuleucel-T相比,ENZ可显著延长PFS;与安慰剂相比,显著增加高血压和疲劳的发生风险。对于转移性激素敏感性前列腺癌(mHSPC),与雄激素剥夺治疗(ADT)、多西他赛联合ADT相比,ENZ联合ADT可显著延长PFS和OS。经济性方面,与阿比特龙相比,ENZ治疗化疗初治或内脏mCRPC患者具有成本-效果优势。结论:ENZ治疗前列腺癌具有良好的有效性和安全性,经济性有待进一步研究。
基金the 2016 Shanghai Pujiang Talent program (No. 16PJ1432800)China State Institute of Pharmaceutical Institute Industry for financially supporting this program
文摘An improved and practical synthesis of enzalutamide was accomplished in five steps.Starting from 4-bromo-2-fluoro-benzonic acid,a methyl esterification,Ullmann ligation,methyl esterification,ring closing reaction and final methyl amidation provided the target in 35% total yield with 99.8% purity.Five identified impurities were also synthesized.This efficient and economical procedure avoids the use of highly toxic reagents and multiple recrystallization operations,which is suitable for further industrialization.
