Molecular disruption of NBS1 with targeted gene delivery enhances chemosensitisation in head and neck cancer.
Molecular disruption of NBS1 with targeted gene delivery enhances chemosensitisation in head and neck cancer.
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DOI：
10.1038/sj.bjc.6605980
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发表时间：
2010-12-07
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
以成纤维细胞生长因子2 （FGF2）为靶点的腺病毒系统可以改变病毒的趋向性，改善转导，降低全身毒性。本研究旨在探讨fgf2靶向的腺病毒突变型奈梅根断裂综合征1 （FGF2-Ad-NBS1）基因转移是否不仅可以通过靶向DNA修复，还可以通过诱导抗血管生成来增强顺铂的化学致敏性，同时降低头颈部鳞状细胞癌（HNSCC）的毒性。人HNSCC细胞系在体外和裸鼠异种移植模型中处理。我们验证了突变体NBS1的结合能力和MRN复合物的下调，评估了转导效率和联合抗肿瘤活性。并对其抗血管生成机制进行了探讨。最后，我们估计了腺病毒载体在肝脏中的分布。突变体NBS1蛋白保留了结合能力，并有效抑制了MRN在感染细胞中的表达水平。体外转导效率和顺铂化敏化上调。FGF2-Ad-NBS1也能使病毒载体脱离肝脏。NF-κB表达下调可能与抗血管生成增加有关。fgf2靶向腺病毒系统增强突变体NBS1的顺铂化学致敏性，并可能避免病毒相关的肝脏毒性。
A fibroblast growth factor 2 (FGF2)-targeted adenoviral system can alter viral tropism and allow for improved transduction and reduced systemic toxicity. This study is to investigate if the FGF2-targeted adenoviral mutant Nijmegen breakage syndrome 1 (FGF2-Ad-NBS1) gene transfer can enhance cisplatin chemosensitisation not only by targeting DNA repair, but also through the induction of antiangiogenesis, whereas at the same time reducing toxicities in treating head and neck squamous cell carcinoma (HNSCC). The human HNSCC cell line was treated in vitro and in a nude mouse xenograft model. We conducted verification of binding ability of mutant NBS1 and downregulation of MRN complex, evaluation of transduction efficiency and combined antitumour activities. The antiangiogenesis mechanism was also investigated. Finally, we estimated the distribution of adenoviral vector in the liver. The mutant NBS1 protein retains the binding ability and effectively suppresses the expression level of the MRN in infected cells. Transduction efficiency in vitro and cisplatin chemosensitisation were upregulated. The FGF2-Ad-NBS1 also showed detargeting the viral vectors away from the liver. The downregulation of NF-κB expression was supposed to correlate with increased antiangiogenesis. FGF2-targeted adenoviral system enhances the cisplatin chemosensitisation of mutant NBS1 and may avoid viral-associated liver toxicities.
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影响因子：
11.5
作者：
Martin, Lainie P.;Hamilton, Thomas C.;Schilder, Russell J.
通讯作者：
Schilder, Russell J.
影响因子：
56.9
作者：
BROWN, K;GERSTBERGER, S;SIEBENLIST, U
通讯作者：
SIEBENLIST, U
影响因子：
5.7
作者：
Li, Bin;Li, Yuk Yin;Cheung, Annie L. M.
通讯作者：
Cheung, Annie L. M.
影响因子：
4.8
作者：
Drummond, JT;Anthoney, A;Modrich, P
通讯作者：
Modrich, P
影响因子：
4.8
作者：
Doukas, J;Hoganson, DK;Sosnowski, BA
通讯作者：
Sosnowski, BA