Combination therapy of prostate cancer with HPMA copolymer conjugates containing PI3K/mTOR inhibitor and docetaxel.
Combination therapy of prostate cancer with HPMA copolymer conjugates containing PI3K/mTOR inhibitor and docetaxel.
复制标题
前列腺癌与含有PI3K/MTOR抑制剂和多西他赛的HPMA共聚物结合物的联合疗法。
DOI：
10.1016/j.ejpb.2014.11.025
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Kopeček J
中科院分区：
文献类型：
--
作者：
Zhou Y;Yang J;Zhang R;Kopeček J
已经研究了组合疗法以解决抗癌疗法的当前挑战。特别是，靶向癌症干/祖细胞和大块肿瘤细胞的联合治疗的新范例有希望改善针对前列腺癌的长期治疗益处。在具有抗CSC活性的治疗剂中，PI 3 K/mTOR抑制剂表现出对前列腺癌干/祖细胞的优先抑制作用和对大量肿瘤细胞的强效细胞毒性。PI 3 K/mTOR抑制剂与传统化疗药物多西他赛联合治疗可能显示出上级单药治疗的疗效。为了进一步提高组合抗肿瘤和抗CSC效果，我们开发了包含两种HPMA共聚物-药物缀合物的组合疗法，分别掺入PI 3 K/mTOR抑制剂GDC-0980（P-（GDC-0980））和多西他赛（P-DTX）。在体外和裸鼠PC-3前列腺癌异种移植物上研究了单一和联合治疗的抗肿瘤和抗CSC作用。我们的评估显示，P-（GDC-0980）抑制CD 133+前列腺干细胞/祖细胞生长，即使在低剂量下也不会引起大量肿瘤细胞的显著生长抑制。联合治疗在体外表现出有效的抗CSC作用以及增强的抗肿瘤作用。在所有游离药物和缀合物的单一和联合给药方案中，大分子联合治疗显示出显着延长小鼠体内生存期。
Combination therapies have been investigated to address the current challenges of anti-cancer therapeutics. In particular, a novel paradigm of combination therapy targeting both cancer stem/progenitor cells and bulk tumor cells is promising to improve the long-term therapeutic benefit against prostate cancer. Among the therapeutic agents with anti-CSC activities, the PI3K/mTOR inhibitors exhibit preferential inhibitory effect on prostate cancer stem/progenitor cells and potent cytotoxicity against bulk tumor cells. The combination of PI3K/mTOR inhibitor and traditional chemotherapy docetaxel may show superior therapeutic effect over single drug treatment. Aiming to further improve the combinational anti-tumor and anti-CSC effect, we developed the combination therapy containing two HPMA copolymer–drug conjugates, incorporated with PI3K/mTOR inhibitor GDC-0980 (P-(GDC-0980)) and docetaxel (P-DTX), respectively. The anti-tumor and anti-CSC effects of the single and combination therapy were investigatedin vitroand on PC-3 prostate cancer xenografts in nude mice. Our evaluations showed that P-(GDC-0980) suppressed CD133+ prostate stem/progenitor cell growth even at the low dose which does not cause significant growth inhibition in bulk tumor cells. The combination therapy exhibited effective anti-CSC effect as well as enhanced anti-bulk tumor effectin vitro. Among all the single and combination dosing regimens of free drugs and conjugates, the macromolecular combination therapy showed significantly prolonged mice survivalin vivo.
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影响因子：
11.5
作者：
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