Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells.
Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells.
复制标题
缺氧靶向三重自杀基因疗法使人类结直肠癌细胞放射增敏。
DOI：
10.3892/or.2014.3238
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发表时间：
2014-08
期刊：
影响因子：
4.2
通讯作者：
Li GC
中科院分区：
文献类型：
--
作者：
Hsiao HT;Xing L;Deng X;Sun X;Ling CC;Li GC
低氧微环境是人类实体瘤的一个重要特征，但在正常组织中不存在，这可能为癌症特异性基因治疗提供机会。本研究的目的是探讨低氧驱动的三重自杀基因TK/CD/UPRT表达是否增强更昔洛韦（GCV）和5-氟胞嘧啶（5-FC）的细胞毒性，并在体外和体内对人大肠癌辐射增敏。建立了低氧诱导表达载体（HRE-TK/eGFP和HRE-CD/UPRT/mDsRed）的人结肠直肠HCT 8细胞的稳定转染子。通过Western blot分析、流式细胞术、荧光显微镜和GCV和5-FC的细胞毒性试验验证缺氧诱导的TK、CD和UPRT的表达/功能。在低氧条件下，5-FC和GCV处理后检测到显着的放射增敏作用。在肿瘤异种移植物中，用荧光显微镜观察的TK/eGFP和CD/UPRT/mDsRed表达的分布与缺氧标记物哌莫硝唑阳性染色细胞共定位。此外，与单独的前药或放射治疗相比，5-FC和GCV联合局部照射对小鼠的给药导致肿瘤消退。我们的数据表明，缺氧诱导的TK/GCV+CDUPRT/5-FC三联自杀基因治疗可能具有特异性靶向缺氧癌细胞的能力，并与放射治疗联合显著提高肿瘤控制。
The hypoxic microenvironment, an important feature of human solid tumors but absent in normal tissue, may provide an opportunity for cancer-specific gene therapy. The purpose of the present study was to investigate whether hypoxia-driven triple suicide gene TK/CD/UPRT expression enhances cytotoxicity to ganciclovir (GCV) and 5-fluorocytosine (5-FC), and sensitizes human colorectal cancer to radiation in vitro and in vivo. Stable transfectant of human colorectal HCT8 cells was established which expressed hypoxia-inducible vectors (HRE-TK/eGFP and HRE-CD/UPRT/mDsRed). Hypoxia-induced expression/function of TK, CD and UPRT was verified by western blot analysis, flow cytometry, fluorescent microscopy and cytotoxicity assay of GCV and 5-FC. Significant radiosensitization effects were detected after 5-FC and GCV treatments under hypoxic conditions. In the tumor xenografts, the distribution of TK/eGFP and CD/UPRT/mDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC and GCV in mice in combination with local irradiation resulted in tumor regression, as compared with prodrug or radiation treatments alone. Our data suggest that the hypoxia-inducible TK/GCV+CDUPRT/5-FC triple suicide gene therapy may have the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy.
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影响因子：
3.5
作者：
Khatri, Aparajita;Zhang, Bing;Russell, Pamela J.
通讯作者：
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