Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA.
Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA.
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DOI：
10.3978/j.issn.2218-676x.2012.05.02
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发表时间：
2012-06
影响因子：
0.9
通讯作者：
Li CY
中科院分区：
文献类型：
--
作者：
Kon T;Zhang X;Huang Q;Yang Z;Liu S;Yan B;Li F;Wang H;Li CY
肿瘤放射治疗研究中的关键问题之一是使肿瘤细胞对电离辐射的细胞杀伤效应敏感，同时保持正常组织完整。实现这一目标的一种潜在方法是通过肿瘤特异性靶向DNA修复基因。在这项研究中，我们设计了一个复制缺陷型腺病毒编码一个小的shRNA基因靶向DNA-PKcs基因，这是参与双链断裂DNA修复，并评估其抗肿瘤疗效与放射治疗相结合。我们的shRNA编码腺病毒在下调DNA-PKcs蛋白水平方面显示出显著的功效，该蛋白水平伴随着人HCT 116结肠癌细胞中辐射敏感性的增加。然而，当瘤内递送到异种移植的人肿瘤时，单独或与放射疗法组合观察到病毒的最小抗肿瘤作用，表明非复制型腺病毒在将shRNA基因递送到肿瘤块中的效率低下。当靶向端粒酶阳性肿瘤细胞的条件复制型腺病毒与靶向DNA-PKcs的编码shRNA的非复制型腺病毒联合使用时，肿瘤特异性抗DNA-PKcs shRNA基因表达的效率显着增强。最重要的是，这种增强的shRNA表达导致同时递送的放射治疗的显著抗肿瘤功效。我们的研究结果表明，我们的基于shRNA的DNA-PKcs靶向方法与肿瘤靶向复制型腺病毒组合是一种有前途的方法，使实体瘤对放射治疗敏感。
One of the key issues in cancer radiotherapy research is to sensitize tumor cells to the cell killing effects of ionizing radiation while leaving normal tissues intact. One potential approach to achieve this is through tumor-specific targeting of DNA repair genes. In this study, we engineered a replication-deficient adenovirus encoding a mini shRNA gene targeted to the DNA-PKcs gene, which is involved in double strand break DNA repair, and evaluated its anti-tumor efficacy in combination with radiotherapy. Our shRNA-encoding adenovirus showed significant efficacy in down-regulating the levels of the DNA-PKcs protein that was accompanied by increased radiation sensitivity in the human HCT116 colon cancer cells. However, when delivered intratumorally to xenograft human tumors, minimal anti-tumor effects of the virus were seen either alone or in combination with radiation therapy, suggesting an inefficiency of the non-replicative adenovirus in delivering shRNA genes to the tumor mass. When a conditionally replicative adenovirus targeted to telomerase-positive tumor cells was used in conjunction with the DNA-PKcs-targeted shRNA-encoding non-replicative adenovirus, the efficiency of tumor-specific anti-DNA-PKcs shRNA gene expression was enhanced significantly. Most importantly, this enhanced shRNA expression led to significant anti-tumor efficacy of concurrently delivered radiation therapy. Our results suggest our shRNA-based DNA-PKcs- targeting approach in combination with tumor-targeting replicative adenovirus is a promising method to sensitize solid tumors to radiation therapy.