Molecular disruption of NBS1 with targeted gene delivery enhances chemosensitisation in head and neck cancer.
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-κB 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.
Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania School of Medicine, 415 Curie Boulevard, CRB Room 145, Philadelphia, PA 19104, USA.
K
K
Araki
T
T
Yamashita
N
N
Reddy
H
H
Wang
W M
WM
Abuzeid
K
K
Khan
B W
BW
O'Malley
D
D
Li
D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D045643:DNA Repair Enzymes / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000821:virology; D000076228:MRE11 Homologue Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D016222:Fibroblast Growth Factor 2; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes; D002945:Cisplatin