Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer
Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer
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DOI：
10.1038/cgt.2012.4
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发表时间：
2012-05-01
影响因子：
6.4
通讯作者：
Medin, J. A.
中科院分区：
文献类型：
--
作者：
Neschadim, A.;Wang, J. C. M.;Medin, J. A.
通过靶向或局部递送“自杀”基因，可以增强化疗药物针对实体瘤的活性和特异性。表达“自杀”基因的细胞中特定前药的选择性激活可通过细胞凋亡驱动其消除，同时也能够杀死邻近的旁观者细胞。强大的旁观者效应可以补偿不良的“自杀”基因传递，并且取决于所使用的前药和旁观者群体获取激活药物的机制，例如间隙连接细胞间通讯的存在。尽管已经开发并表征了许多针对癌症的“自杀”基因疗法，例如基于单纯疱疹病毒衍生胸苷激酶（HSV-tk）的更昔洛韦激活，但其有限的成功凸显了开发更强大方法的必要性。限制活化动力学和化学抗性的演变是主要障碍。在这里，我们描述了基于慢病毒介导的胸苷活性人脱氧胞苷激酶变体的癌症“自杀”基因治疗。这种酶具有底物可塑性，使其能够激活多种前药，其中一些前药具有不同的作用机制。我们评估了不同前药引起的旁观者效应的程度和机制，并表明当组合使用时，它们可以协同增强旁观者效应，同时避免脱靶毒性。
Activity and specificity of chemotherapeutic agents against solid tumors can be augmented via the targeted or localized delivery of 'suicide' genes. Selective activation of specific prodrugs in cells expressing the 'suicide' gene drives their elimination by apoptosis, while also enabling the killing of adjacent bystander cells. Strong bystander effects can compensate for poor 'suicide' gene delivery, and depend on the prodrugs used and mechanisms for the acquisition of activated drug by the bystander population, such as the presence of gap junctional intercellular communications. Although a number of 'suicide' gene therapies for cancer have been developed and characterized, such as herpes simplex virus-derived thymidine kinase (HSV-tk)-based activation of ganciclovir, their limited success highlights the need for the development of more robust approaches. Limiting activation kinetics and evolution of chemoresistance are major obstacles. Here we describe 'suicide' gene therapy of cancer based on the lentivirus-mediated delivery of a thymidine-active human deoxycytidine kinase variant. This enzyme possesses substrate plasticity that enables it to activate a multitude of prodrugs, some with distinct mechanisms of action. We evaluated the magnitude and mechanisms of bystander effects induced by different prodrugs, and show that when used in combination, they can synergistically enhance the bystander effect while avoiding off-target toxicity.