Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania School of Medicine, 415 Curie Boulevard, CRB Room 145, Philadelphia, PA 19104, USA.
Br J Cancer. 2010 Dec 7;103(12):1822-30. doi: 10.1038/sj.bjc.6605980. Epub 2010 Nov 9.
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.
成纤维细胞生长因子 2（FGF2）靶向的腺病毒系统可以改变病毒的嗜性，从而提高转导效率，降低全身毒性。本研究旨在探讨 FGF2 靶向的腺病毒突变体 Nijmegen 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化疗敏感性，同时降低治疗头颈部鳞状细胞癌（HNSCC）的毒性。
体外和裸鼠异种移植模型中处理人 HNSCC 细胞系。我们验证了突变型 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。还研究了抗血管生成的机制。最后，我们估计了腺病毒载体在肝脏中的分布。
突变型 NBS1 蛋白保留了结合能力，并有效地抑制了感染细胞中 MRN 的表达水平。体外转导效率和顺铂化疗增敏作用上调。FGF2-Ad-NBS1 还显示出将病毒载体脱靶远离肝脏。NF-κB 表达的下调可能与抗血管生成增加有关。
FGF2 靶向的腺病毒系统增强了突变型 NBS1 的顺铂化疗增敏作用，并可能避免与病毒相关的肝脏毒性。
