Therapeutic Effect of Sodium Iodide Symporter Gene Therapy Combined With External Beam Radiotherapy and Targeted Drugs That Inhibit DNA Repair
Therapeutic Effect of Sodium Iodide Symporter Gene Therapy Combined With External Beam Radiotherapy and Targeted Drugs That Inhibit DNA Repair
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DOI：
10.1038/mt.2010.120
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发表时间：
2010-09-01
影响因子：
12.4
通讯作者：
Harrington, Kevin J.
中科院分区：
文献类型：
--
作者：
Hingorani, Mohan;White, Christine L.;Harrington, Kevin J.
腺病毒（AdV）转移钠碘转运体（NIS）基因具有翻译潜力，但相对较低的转导水平和随后的放射性同位素摄取限制了该方法的有效性。在以前的研究中，我们表明，NIS基因的传递与外照射放疗（EBRT）和DNA损伤修复抑制剂相结合，增加了病毒基因的表达和放射性碘的摄取。在这里，我们报告了这种策略的治疗效果。从端粒酶启动子表达NIS的腺病毒（Ad-hTR-NIS）与相对高剂量（50 μ Ci）的I-131治疗相结合具有细胞毒性，并增强了EBRT与低剂量（10和25 μ Ci）I-131治疗相结合在结直肠癌和头颈部癌细胞中的疗效。将这种方法与共济失调-毛细血管扩张突变（ATM）或DNA依赖性蛋白激酶（DNA-PK）抑制相结合，导致在24小时时维持双链DNA断裂（DSB），并增加克隆形成试验的细胞毒性。当在体内使用NIS介导的I-131治疗、EBRT和DNA-PKi的三联体时，90%的小鼠在5周时无肿瘤。EBRT场中的急性辐射毒性未加重。相比之下，DNA-PKi没有增强EBRT加腺病毒介导的HSVtk/更昔洛韦（GCV）的治疗效果。因此，NIS基因治疗和EBRT相结合是开发新型放射增敏剂治疗益处的理想策略。
Adenoviral (AdV) transfer of sodium iodide symporter (NIS) gene has translational potential, but relatively low levels of transduction and subsequent radioisotope uptake limit the efficacy of the approach. In previous studies, we showed that combining NIS gene delivery with external beam radiotherapy (EBRT) and DNA damage repair inhibitors increased viral gene expression and radioiodide uptake. Here, we report the therapeutic efficacy of this strategy. An adenovirus expressing NIS from a telomerase promoter (Ad-hTR-NIS) was cytotoxic combined with relatively high-dose (50 mu Ci) I-131 therapy and enhanced the efficacy of EBRT combined with low-dose (10 and 25 mu Ci) I-131 therapy in colorectal and head and neck cancer cells. Combining this approach with ataxia-telangiectasia mutated (ATM) or DNA-dependent protein kinase (DNA-PK) inhibition caused maintenance of double-stranded DNA breaks (DSBs) at 24 hours and increased cytotoxicity on clonogenic assay. When the triplet of NIS-mediated I-131 therapy, EBRT, and DNA-PKi was used in vivo, 90% of mice were tumor-free at 5 weeks. Acute radiation toxicity in the EBRT field was not exacerbated. In contrast, DNA-PKi did not enhance the therapeutic efficacy of EBRT plus adenovirus-mediated HSVtk/ganciclovir (GCV). Therefore, combining NIS gene therapy and EBRT represents an ideal strategy to exploit the therapeutic benefits of novel radiosensitizers.