Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer.
Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer.
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DOI：
10.1186/1471-2407-11-221
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发表时间：
2011-06-06
期刊：
影响因子：
3.8
通讯作者：
Pandha HS
中科院分区：
文献类型：
--
作者：
Heinemann L;Simpson GR;Boxall A;Kottke T;Relph KL;Vile R;Melcher A;Prestwich R;Harrington KJ;Morgan R;Pandha HS
呼肠孤病毒3型Dearing（T3 D）已经在体外、体内鼠模型和早期临床试验中证明了溶瘤活性。然而，溶瘤病毒的真正潜力只有与其他方式如化疗、靶向治疗和放疗联合使用才能充分发挥。在这项研究中，我们研究了呼肠孤病毒T3 D和化疗药物对人前列腺癌细胞系的溶瘤活性，特别关注高转移性细胞系PC 3和化疗药物多西他赛。多西他赛是转移性前列腺癌的标准治疗药物，通过破坏微管组装和拆卸的正常过程发挥作用。呼肠孤病毒已被证明与微管相关，并且可能需要这种相关以进行有效的病毒复制。在PC 3和Du 145细胞中研究呼肠孤病毒和化疗对体外细胞毒性的影响，并通过组合指数分析评估药物之间的相互作用。使用基于膜联蛋白V/碘化丙啶荧光激活细胞分选的测定来确定细胞死亡模式。在鼠模型中体内测试作为单一药剂或组合疗法施用的呼肠孤病毒和多西他赛的作用。多西他赛和呼肠孤病毒，单独和一起，对微管稳定的影响进行了研究，通过蛋白质印迹分析。在暴露于活呼肠孤病毒和几种化疗剂的PC 3和Du 145细胞中观察到不同程度的协同细胞毒性。呼肠孤病毒感染与多西他赛暴露的组合导致晚期凋亡/坏死细胞群增加。呼肠孤病毒/多西他赛联合治疗导致携带PC 3肿瘤的小鼠模型中肿瘤生长减少和存活增加。与其他呼肠孤病毒/化疗组合相比，用呼肠孤病毒/多西他赛联合治疗的PC 3细胞中微管稳定性增强。多种化疗剂与活呼肠孤病毒的共同施用能够在体外协同增强细胞毒性。多西他赛与呼肠孤病毒的组合也延迟了肿瘤生长并提高了体内存活率。这种联合治疗后微管稳定性的增强可能部分解释了协同作用的机制。这些结果为使用这些药物进行的临床试验提供了证据。
Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication. The effects of reovirus and chemotherapy on in vitro cytotoxicity were investigated in PC3 and Du 145 cells and the interactions between agents were assessed by combination index analysis. An Annexin V/propidium iodide fluorescence-activated cell sorting-based assay was used to determine mode of cell death. The effects of reovirus and docetaxel administered as single agent or combination therapy were tested in vivo in a murine model. The effects of docetaxel and reovirus, alone and together, on microtubule stabilisation were investigated by Western blot analysis. Variable degrees of synergistic cytotoxicity were observed in PC3 and Du 145 cells exposed to live reovirus and several chemotherapy agents. Combination of reovirus infection with docetaxel exposure led to increased late apoptotic/necrotic cell populations. Reovirus/docetaxel combined therapy led to reduced tumour growth and increased survival in a PC3 tumour bearing mouse model. Microtubule stabilization was enhanced in PC3 cells treated with reovirus/docetaxel combined therapy compared to other reovirus/chemotherapy combinations. The co-administration of a variety of chemotherapeutic agents with live reovirus was able to enhance cytotoxicity synergistically in vitro. The combination of docetaxel with reovirus also delayed tumour growth and improved survival in vivo. Enhanced microtubule stabilisation following this combination treatment may, in part, explain the mechanism of synergy. These results provide evidence to support the ongoing clinical trials using these agents.
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2.7
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HASHIRO, G;LOH, PC;YAU, JT
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