Molecular disruption of NBS1 with targeted gene delivery enhances chemosensitisation in head and neck cancer

作者：Araki K; Yamashita T; Reddy N; Wang H; Abuzeid W M; Khan K; O'Malley B W Jr; Li D^*

来源：British Journal of Cancer, 2010, 103(12): 1822-1830.

DOI：10.1038/sj.bjc.6605980

• chemoresistance
• NBS1
• adenovirus
• targeted gene therapy
• DNA double-strand breaks
• DNA repair

BACKGROUND: 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).
METHODS: 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.
RESULTS: 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-kappa B expression was supposed to correlate with increased antiangiogenesis.
CONCLUSIONS: FGF2-targeted adenoviral system enhances the cisplatin chemosensitisation of mutant NBS1 and may avoid viral-associated liver toxicities. British Journal of Cancer (2010) 103, 1822-1830. doi:10.1038/sj.bjc.6605980 www.bjcancer.

• 出版日期2010-12-7