Park Seung-Yoon, Lee Wan, Lee Jaetae, Kim In-San
Department of Biochemistry, School of Medicine, Dongguk University, Kyungju 780-714, Republic of Korea.
Cancer Lett. 2008 Mar 18;261(2):205-14. doi: 10.1016/j.canlet.2007.11.011. Epub 2007 Dec 21.
The current study was designed to evaluate the anti-tumor effects of MDR1 shRNA in combination with herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) suicide gene therapy system. Introduction of an MDR1-targeted small hairpin RNA (shMDR) markedly enhanced the intracellular accumulation of and increased sensitivity to drugs transported by P-glycoprotein. Functional TK-eGFP fusion protein expression was confirmed by Western blot analysis and ganciclovir uptake assay. Compared with GCV or doxorubicin alone, the combination of anti-cancer drug chemotherapy with GCV administration displays additive cytotoxicity in shMDR1-TK-eGFP expressing cells. These results for the first time suggest the potential of combination gene therapy using suicide gene therapy and RNAi-based gene therapy in vitro.
本研究旨在评估多药耐药蛋白1（MDR1）短发夹RNA（shRNA）与单纯疱疹病毒胸苷激酶/更昔洛韦（HSV-tk/GCV）自杀基因治疗系统联合应用的抗肿瘤作用。导入靶向MDR1的小发夹RNA（shMDR）可显著增强细胞内P-糖蛋白转运药物的蓄积并提高对这些药物的敏感性。通过蛋白质免疫印迹分析和更昔洛韦摄取试验证实了功能性胸苷激酶-增强绿色荧光蛋白（TK-eGFP）融合蛋白的表达。与单独使用更昔洛韦或阿霉素相比，抗癌药物化疗与更昔洛韦联合给药在表达shMDR1-TK-eGFP的细胞中显示出相加的细胞毒性。这些结果首次表明在体外将自杀基因治疗与基于RNA干扰的基因治疗联合应用进行基因治疗具有潜在可能性。
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