The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PT...The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PTX-S-DOX(PSD).The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX.Thus,we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation.Due to the fact that copper ions(Cu2+)could coordinate with the anthracene nucleus of DOX,we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+gradient.Hence,we designed a remote loading liposomal formulation of PSD(PSD LPs)for combination chemotherapy.The prepared PSD LPs displayed extended blood circulation,improved tumor accumulation,and more significant anti-tumor efficacy compared with PSD NPs.Furthermore,PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil,indicating better safety.Therefore,this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.展开更多
Background Cancer cells with overexpression of heat shock protein 27 （HSP27） are resistant to chemotherapeutic drug doxorubicin （Dox）. Paclitaxel （Pacl） was reported to suppress HSP27 expression in ovarian and u...Background Cancer cells with overexpression of heat shock protein 27 （HSP27） are resistant to chemotherapeutic drug doxorubicin （Dox）. Paclitaxel （Pacl） was reported to suppress HSP27 expression in ovarian and uterine cancer cells. The purposes of this study were to investigate whether Pacl inhibits the expression of HSP27 in breast cancer cells, whether Pacl can sensitize breast cancer cells with HSP27 overexpression to Dox, and to define a more effective schedule for the combination of Dox with Pacl. Methods The HSP27 high-expressing human breast cancer cell lines, MCF-7 and MDA-MB-435, and the HSP27 low-expressing cell line, MDA-MB-231, were used in this study. The level of HSP27, topoisomerase （Topo） IIα and β expression were assessed by Western blotting. The cytotoxic activities of Dox, Pacl and combination of these two drugs were evaluated by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay and flow cytometric assays. Results Pacl （0.1 μmol/L） inhibited HSP27 expression by approximately 2-fold in MCF-7 and MDA-MB-435 cells, while up-regulating the level of topo IIα and β. In contrast, expression of HSP27 in MDA-MB-231 did not change significantly following Pacl treatment. There were synergistic effects in both treatment sequences （Pacl-Dox and Dox-Pacl） when Pacl was combined with Dox. Compared with those treated with the Dox-Pacl sequence, the Pacl-Dox sequence had a stronger effect in cancer cells with HSP27 overexpression, as MCF-7 and MDA-MB-435 treated with the Pacl-Dox sequence had lower viabilities and a higher apoptotic rate. Conclusions Paclitaxel significantly decreases the level of HSP27 in breast cancer cells overexpressing HSP27. In combination therapies, the Pacl-Dox sequence is more effective in clearing breast cancer cells with high HSP27 expression compared with the Dox-Pacl sequence.展开更多
目的：系统评价脂质体多柔比星联合卡铂治疗卵巢癌的疗效及安全性。方法：计算机检索Cochrane Library、Pubmed、EMbase、Web of Science、中国CNKI学术总库、万方数据库、维普中文科技期刊数据库和中国生物医学文献数据库，检索时间从...目的：系统评价脂质体多柔比星联合卡铂治疗卵巢癌的疗效及安全性。方法：计算机检索Cochrane Library、Pubmed、EMbase、Web of Science、中国CNKI学术总库、万方数据库、维普中文科技期刊数据库和中国生物医学文献数据库，检索时间从建库截至2013年3月，同时追索纳入文献的参考文献，查找脂质体多柔比星联合卡铂及紫杉醇联合卡铂治疗卵巢癌的随机对照试验（RCT）。由2位研究者按照纳入、排除标准筛选文献，提取资料并依据CochraneHand—book5．0．1质量评价标准评价纳入文献后，采用RevMan5．1软件进行Meta分析。结果：纳入3个临床RCT，共1985例患者。Meta分析结果显示：总生存率两组差异无统计学意义（OR=0．85，95％C10．71～1．02，P=0．090），与紫杉醇联合卡铂相比，脂质体多柔比星联合卡铂治疗改善患者的中位无进展生存率（OR=1．15，95％CI1．03～1．30，P=0．020）效果更好，过敏反应（OR=0．28，95％C10．19—0．41，P=0．000）、脱发（0R=0．08，95％C10．06～0．10，P=0．000）、中性白细胞减少（OR=0．70，95％C10．58—0．84，P=0．000）和神经毒性（OR=0．17，95％C10．14～0．21，P=0．000）发生较少，但用药期间掌跖红斑（OR=3．82，95％CI2．85～5．13，P=0．000）和血小板减少症（OR=4．31，95％CI3．00～6．17，P=0．000）的发生却明显增加。结论：脂质体多柔比星联合卡铂与紫杉醇联合卡铂治疗卵巢癌的总体生存率相当，而中位无进展生存情况脂质体多柔比星联合卡铂有明显优势，且部分毒副反应明显减轻。展开更多
基金supported by National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2017ZX09101-001-005,Beijing,China)Science and Technology Plan Project of Shenyang(No.18-400-4-08,Z17-5-064,China)the Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University(Shenyang,China)
文摘The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PTX-S-DOX(PSD).The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX.Thus,we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation.Due to the fact that copper ions(Cu2+)could coordinate with the anthracene nucleus of DOX,we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+gradient.Hence,we designed a remote loading liposomal formulation of PSD(PSD LPs)for combination chemotherapy.The prepared PSD LPs displayed extended blood circulation,improved tumor accumulation,and more significant anti-tumor efficacy compared with PSD NPs.Furthermore,PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil,indicating better safety.Therefore,this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.
文摘Background Cancer cells with overexpression of heat shock protein 27 （HSP27） are resistant to chemotherapeutic drug doxorubicin （Dox）. Paclitaxel （Pacl） was reported to suppress HSP27 expression in ovarian and uterine cancer cells. The purposes of this study were to investigate whether Pacl inhibits the expression of HSP27 in breast cancer cells, whether Pacl can sensitize breast cancer cells with HSP27 overexpression to Dox, and to define a more effective schedule for the combination of Dox with Pacl. Methods The HSP27 high-expressing human breast cancer cell lines, MCF-7 and MDA-MB-435, and the HSP27 low-expressing cell line, MDA-MB-231, were used in this study. The level of HSP27, topoisomerase （Topo） IIα and β expression were assessed by Western blotting. The cytotoxic activities of Dox, Pacl and combination of these two drugs were evaluated by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay and flow cytometric assays. Results Pacl （0.1 μmol/L） inhibited HSP27 expression by approximately 2-fold in MCF-7 and MDA-MB-435 cells, while up-regulating the level of topo IIα and β. In contrast, expression of HSP27 in MDA-MB-231 did not change significantly following Pacl treatment. There were synergistic effects in both treatment sequences （Pacl-Dox and Dox-Pacl） when Pacl was combined with Dox. Compared with those treated with the Dox-Pacl sequence, the Pacl-Dox sequence had a stronger effect in cancer cells with HSP27 overexpression, as MCF-7 and MDA-MB-435 treated with the Pacl-Dox sequence had lower viabilities and a higher apoptotic rate. Conclusions Paclitaxel significantly decreases the level of HSP27 in breast cancer cells overexpressing HSP27. In combination therapies, the Pacl-Dox sequence is more effective in clearing breast cancer cells with high HSP27 expression compared with the Dox-Pacl sequence.
文摘目的：系统评价脂质体多柔比星联合卡铂治疗卵巢癌的疗效及安全性。方法：计算机检索Cochrane Library、Pubmed、EMbase、Web of Science、中国CNKI学术总库、万方数据库、维普中文科技期刊数据库和中国生物医学文献数据库，检索时间从建库截至2013年3月，同时追索纳入文献的参考文献，查找脂质体多柔比星联合卡铂及紫杉醇联合卡铂治疗卵巢癌的随机对照试验（RCT）。由2位研究者按照纳入、排除标准筛选文献，提取资料并依据CochraneHand—book5．0．1质量评价标准评价纳入文献后，采用RevMan5．1软件进行Meta分析。结果：纳入3个临床RCT，共1985例患者。Meta分析结果显示：总生存率两组差异无统计学意义（OR=0．85，95％C10．71～1．02，P=0．090），与紫杉醇联合卡铂相比，脂质体多柔比星联合卡铂治疗改善患者的中位无进展生存率（OR=1．15，95％CI1．03～1．30，P=0．020）效果更好，过敏反应（OR=0．28，95％C10．19—0．41，P=0．000）、脱发（0R=0．08，95％C10．06～0．10，P=0．000）、中性白细胞减少（OR=0．70，95％C10．58—0．84，P=0．000）和神经毒性（OR=0．17，95％C10．14～0．21，P=0．000）发生较少，但用药期间掌跖红斑（OR=3．82，95％CI2．85～5．13，P=0．000）和血小板减少症（OR=4．31，95％CI3．00～6．17，P=0．000）的发生却明显增加。结论：脂质体多柔比星联合卡铂与紫杉醇联合卡铂治疗卵巢癌的总体生存率相当，而中位无进展生存情况脂质体多柔比星联合卡铂有明显优势，且部分毒副反应明显减轻。
文摘目的评价托泊替康在复发性卵巢癌化疗中的疗效,安全性以及成本效果。方法计算机检索MEDLINE(1966～2005),EMbase(1974～2005), CancerLit(1996～2003),中国生物医学文献数据库(1978-2005)。中国期刊全文数据库(1 994～2005),The Cochrane Central Register of Controlled Trials(CENTRAL),The National Research Register,Health Technology Assessment Database(HTA),Cochrane图书馆(2005年第3期)等数据库。手工检索相关领域的杂志,并用Google等搜索引擎在互联网上查找相关的文献。检索截止至2005年12月。收集有关托泊替康(TPT)与其他药物比较治疗复发性卵巢癌(ROC)的随机对照试验(RcT)文献。由两名研究者独立评价纳入研究的文献质量,并提取有效数据进行Meta分析。结果共纳入4个RCT(9篇文献,1 032例病人)。其中1个多中心RCT(474例,B级),比较TPT与脂质体阿霉素(PLD)治疗ROC的疗效和成本;另1个多中心RCT(226例,A级),比较托泊替康与紫杉醇的疗效。还有1个RCT (266例,B级)为TPT不同用药途径的比较;最后1个RCT(66例,A级)比较了TPT两种用药方案及剂量。结果显示:①TPT与紫杉醇比较:临床受益率TPT大于紫杉醇,两者差异有统计学意义;缓解率、疾病稳定率的差异无统计学意义;3／4级血液学毒性TPT高于紫杉醇,对铂类耐药者TPT的生存时间长于紫杉醇,差异有统计学意义;两者生存质量差异无统计学意义。②TPT与PLD比较:临床受益率、缓解率差异无统计学意义。3／4级血液学毒性,TPT高于PLD,差异有统计学意义。对铂类敏感者TPT组的生存时间短于PLD组:1年生存率差异无统计学意义;2、3年生存率TPT低于PLD,差异有统计学意义。成本效果分析:TPT的治疗总成本高于PLD;二者生活质量差异无统计学意义。③TPT两种用药剂量(方案)的比较:标准方案的缓解率及3／4级中性粒细胞减少的血液学毒性均大于24 h静滴方案;生存时间差异无统计学意义。④TPT口服与静脉两种用药途径相比:总缓解率静脉途径大于口服途径;口服途径的中性粒细胞减少的血液学毒性小于静脉途径,生存时间短于静脉途径。结论在ROC的化疗中,TPT的疗效优于紫杉醇,与PLD相当(TPT的临床受益率大于紫杉醇,缓解率相当于紫杉醇,对铂类耐药ROC患者TPT治疗的生存率大于紫杉醇)。TPT的缓解率和临床受益率与PLD差异无统计学意义,TPT的2、3年生存率低于PLD,铂类敏感的生存时间小于PLD;血液学毒性TPT大于紫杉醇和PLD;治疗成本TPT高于PLD。关于TPT在ROC的二线化疗中的临床应用,推荐用于耐药性、难治性的卵巢癌,选用治疗效果足够、毒性可以耐受的5天静脉滴注的标准治疗方案。
