Sequence-dependent combination therapy with doxorubicin and a survivin-specific small interfering RNA nanodrug demonstrates efficacy in models of adenocarcinoma.
Sequence-dependent combination therapy with doxorubicin and a survivin-specific small interfering RNA nanodrug demonstrates efficacy in models of adenocarcinoma.
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DOI：
10.1002/ijc.28499
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发表时间：
2014-04-01
影响因子：
6.4
通讯作者：
Medarova, Zdravka
中科院分区：
文献类型：
--
作者：
Ghosh, Subrata K.;Yigit, Mehmet V.;Uchida, Masashi;Ross, Alana W.;Barteneva, Natalie;Moore, Anna;Medarova, Zdravka
癌症的临床管理反映了治疗效果和毒性之间的平衡。虽然通常情况下，与序贯单一疗法相比，联合疗法可以提高缓解率和进展时间，但它会导致毒性增加。因此，对于晚期癌症，新出现的指南建议序贯单一疗法，作为提高生活质量的一种手段。另一种方法可以克服非特异性毒性，同时保留治疗效果，包括化疗与靶向治疗的结合。在当前的研究中，我们测试了这样的假设：与 Dox 单一疗法相比，针对生存素 (BIRC5) 和低剂量阿霉素 (Dox) 的联合疗法将在癌症治疗中显示出增强的治疗潜力。我们在乳腺癌的体外和体内模型中证明，低剂量 Dox 和抗生存素 siRNA 纳米药物 (MN-siBIRC5) 的联合治疗优于单独使用低剂量或高剂量 Dox 的单一治疗。重要的是，治疗效果显示出显着的序列依赖性。仅当用 Dox 处理细胞，然后用 MN-siBIRC5 处理细胞时，才观察到细胞凋亡的诱导，而相反的顺序则消除了药物组合的益处。在体内，在小鼠乳腺癌异种移植模型中证实了序列依赖性联合治疗的成功。最后，为了确定观察到的效果是否不仅限于乳腺癌，我们将研究扩展到胰腺腺癌的小鼠异种移植模型，并发现了与乳腺癌相似的结果。
The clinical management of cancer reflects a balance between treatment efficacy and toxicity. While typically, combination therapy improves response rate and time to progression compared with sequential monotherapy, it causes increased toxicity. Consequently, in cases of advanced cancer, emerging guidelines recommend sequential monotherapy, as a means to enhance quality of life. An alternative approach that could overcome nonspecific toxicity while retaining therapeutic efficacy, involves the combination of chemotherapy with targeted therapy. In the current study, we tested the hypothesis that combination therapy targeting survivin (BIRC5) and low-dose doxorubicin (Dox) will show enhanced therapeutic potential in the treatment of cancer, as compared to monotherapy with Dox. We demonstrate in both in vitro and in vivo models of breast cancer that combination therapy with a low dose of Dox and an anti-survivin siRNA nanodrug (MN-siBIRC5) is superior to mono-therapy with either low- or high-dose Dox alone. Importantly, therapeutic efficacy showed prominent sequence dependence. Induction of apoptosis was observed only when the cells were treated with Dox followed by MN-siBIRC5, whereas the reverse sequence abrogated the benefit of the drug combination. In vivo, confirmation of successful sequence dependent combination therapy was demonstrated in a murine xenografts model of breast cancer. Finally, to determine if the observed effect is not limited to breast cancer, we extended our studies to a murine xenograft model of pancreatic adenocarcinoma and found similar outcomes as shown for breast cancer.
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影响因子：
11.2
作者：
Medarova Z;Rashkovetsky L;Pantazopoulos P;Moore A
通讯作者：
Moore A
影响因子：
11.2
作者：
Kumar M;Yigit M;Dai G;Moore A;Medarova Z
通讯作者：
Medarova Z
影响因子：
5.7
作者：
Smith, Laura;Watson, Mark B.;Cawkwell, Lynn
通讯作者：
Cawkwell, Lynn
影响因子：
6.4
作者：
Ghosh, Subrata K.;Uchida, Masashi;Medarova, Zdravka
通讯作者：
Medarova, Zdravka
影响因子：
8.8
作者：
Sarela, A I;Verbeke, C S;Ramsdale, J;Davies, C L;Markham, A F;Guillou, P J
通讯作者：
Guillou, P J