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

Araki K, Yamashita T, Reddy N, Wang H, Abuzeid WM, Khan K, O'Malley BW, Li D - Br. J. Cancer (2010)

Bottom Line: a fibroblast growth factor 2 (FGF2)-targeted adenoviral system can alter viral tropism and allow for improved transduction and reduced systemic toxicity.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.FGF2-targeted adenoviral system enhances the cisplatin chemosensitisation of mutant NBS1 and may avoid viral-associated liver toxicities.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania School of Medicine, 415 Curie Boulevard, CRB Room 145, Philadelphia, PA 19104, USA.

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Fibroblast growth factor 2-targeted Ad-NBS1 gene transfer sensitizes head and neck cancer with cisplatin-based chemotherapy in vitro and in vivo. Tumour cell growth curve analysis in vitro at an MOI of 5 (A) and 10 (B) in six different treatment groups. Fibroblast growth factor 2-targeted Ad-NBS1 with cisplatin group had the greatest tumour suppression effect at an MOI of 5 (A), whereas no difference was observed between FGF2-Ad-NBS1/Cisplatin and Ad-NBS1/Cisplatin at an MOI of 10 (B). The FGF2-targeted system might enable a lower titre administration. Tumour volume changes before and after treatments are shown in the mouse model. (C) The greatest tumour shrinkage occurred when Ad-NBS1 gene therapy was combined with Regular cisplatin. The tumour treated with Ad-NBS1/Reduced cisplatin also showed better a tumour suppression effect when compared with the regular dose of cisplatin-treated tumours. (D) The combination Ad-NBS1/Regular cisplatin and FGF2-Ad-NBS1/Reduced cisplatin had the greatest efficacy in reducing tumour size and the effect was almost the same in both treatments. Fibroblast growth factor 2-Ad-NBS1 therapy enhances sensitivity for cisplatin intensely and allows for reduction of cisplatin dose. #P<0.01 when compared with Ad-NBS1/Regular dose of cisplatin, ##P<0.05 when compared with Ad-NBS1/Regular dose of cisplatin, +P<0.01 when compared with Ad-NBS1/Reduced dose of cisplatin, ++P<0.05 when compared with Ad-NBS1/Reduced dose of cisplatin, *P<0.01 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin, **P<0.05 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin.
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fig3: Fibroblast growth factor 2-targeted Ad-NBS1 gene transfer sensitizes head and neck cancer with cisplatin-based chemotherapy in vitro and in vivo. Tumour cell growth curve analysis in vitro at an MOI of 5 (A) and 10 (B) in six different treatment groups. Fibroblast growth factor 2-targeted Ad-NBS1 with cisplatin group had the greatest tumour suppression effect at an MOI of 5 (A), whereas no difference was observed between FGF2-Ad-NBS1/Cisplatin and Ad-NBS1/Cisplatin at an MOI of 10 (B). The FGF2-targeted system might enable a lower titre administration. Tumour volume changes before and after treatments are shown in the mouse model. (C) The greatest tumour shrinkage occurred when Ad-NBS1 gene therapy was combined with Regular cisplatin. The tumour treated with Ad-NBS1/Reduced cisplatin also showed better a tumour suppression effect when compared with the regular dose of cisplatin-treated tumours. (D) The combination Ad-NBS1/Regular cisplatin and FGF2-Ad-NBS1/Reduced cisplatin had the greatest efficacy in reducing tumour size and the effect was almost the same in both treatments. Fibroblast growth factor 2-Ad-NBS1 therapy enhances sensitivity for cisplatin intensely and allows for reduction of cisplatin dose. #P<0.01 when compared with Ad-NBS1/Regular dose of cisplatin, ##P<0.05 when compared with Ad-NBS1/Regular dose of cisplatin, +P<0.01 when compared with Ad-NBS1/Reduced dose of cisplatin, ++P<0.05 when compared with Ad-NBS1/Reduced dose of cisplatin, *P<0.01 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin, **P<0.05 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin.

Mentions: The benefit of FGF2-targeted adenoviral system in tumour suppression was investigated using the MTT assay. JHU006 cells were subjected to six interventions. The cell growth in Ad-NBS1/cisplatin and FGF2-Ad-NBS1/cisplatin had a greater inhibition than that in other groups at an MOI of 5 (Figure 3A). The cell growth of Ad-NBS1/cisplatin and FGF2-Ad-NBS1/cisplatin also had a greater inhibition than that of the Control or Cisplatin groups at an MOI of 10 (Figure 3B); however, no difference was observed when compared with that of Ad-NBS1 or FGF2-Ad-NBS1. These results at an MOI of 5 show that the tumour inhibition in FGF2-Ad-NBS1/cisplatin has more effect at an early phase than that of Ad-NBS1/cisplatin. This is consistent with the results of the GFP expression in higher and earlier transduction of FGF2-Ad-NBS1/cisplatin than that of Ad-NBS1/cisplatin. However, the results at an MOI of 10 suggest that the transduction efficiency and tumour growth inhibition reaches the maximum level in Ad-NBS1/cisplatin at an MOI of 10. As a result, the FGF2-targeted system has the potential of a lower titre administration of virus while still achieving optimal cisplatin chemosensitisation effects.


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

Araki K, Yamashita T, Reddy N, Wang H, Abuzeid WM, Khan K, O'Malley BW, Li D - Br. J. Cancer (2010)

Fibroblast growth factor 2-targeted Ad-NBS1 gene transfer sensitizes head and neck cancer with cisplatin-based chemotherapy in vitro and in vivo. Tumour cell growth curve analysis in vitro at an MOI of 5 (A) and 10 (B) in six different treatment groups. Fibroblast growth factor 2-targeted Ad-NBS1 with cisplatin group had the greatest tumour suppression effect at an MOI of 5 (A), whereas no difference was observed between FGF2-Ad-NBS1/Cisplatin and Ad-NBS1/Cisplatin at an MOI of 10 (B). The FGF2-targeted system might enable a lower titre administration. Tumour volume changes before and after treatments are shown in the mouse model. (C) The greatest tumour shrinkage occurred when Ad-NBS1 gene therapy was combined with Regular cisplatin. The tumour treated with Ad-NBS1/Reduced cisplatin also showed better a tumour suppression effect when compared with the regular dose of cisplatin-treated tumours. (D) The combination Ad-NBS1/Regular cisplatin and FGF2-Ad-NBS1/Reduced cisplatin had the greatest efficacy in reducing tumour size and the effect was almost the same in both treatments. Fibroblast growth factor 2-Ad-NBS1 therapy enhances sensitivity for cisplatin intensely and allows for reduction of cisplatin dose. #P<0.01 when compared with Ad-NBS1/Regular dose of cisplatin, ##P<0.05 when compared with Ad-NBS1/Regular dose of cisplatin, +P<0.01 when compared with Ad-NBS1/Reduced dose of cisplatin, ++P<0.05 when compared with Ad-NBS1/Reduced dose of cisplatin, *P<0.01 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin, **P<0.05 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin.
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fig3: Fibroblast growth factor 2-targeted Ad-NBS1 gene transfer sensitizes head and neck cancer with cisplatin-based chemotherapy in vitro and in vivo. Tumour cell growth curve analysis in vitro at an MOI of 5 (A) and 10 (B) in six different treatment groups. Fibroblast growth factor 2-targeted Ad-NBS1 with cisplatin group had the greatest tumour suppression effect at an MOI of 5 (A), whereas no difference was observed between FGF2-Ad-NBS1/Cisplatin and Ad-NBS1/Cisplatin at an MOI of 10 (B). The FGF2-targeted system might enable a lower titre administration. Tumour volume changes before and after treatments are shown in the mouse model. (C) The greatest tumour shrinkage occurred when Ad-NBS1 gene therapy was combined with Regular cisplatin. The tumour treated with Ad-NBS1/Reduced cisplatin also showed better a tumour suppression effect when compared with the regular dose of cisplatin-treated tumours. (D) The combination Ad-NBS1/Regular cisplatin and FGF2-Ad-NBS1/Reduced cisplatin had the greatest efficacy in reducing tumour size and the effect was almost the same in both treatments. Fibroblast growth factor 2-Ad-NBS1 therapy enhances sensitivity for cisplatin intensely and allows for reduction of cisplatin dose. #P<0.01 when compared with Ad-NBS1/Regular dose of cisplatin, ##P<0.05 when compared with Ad-NBS1/Regular dose of cisplatin, +P<0.01 when compared with Ad-NBS1/Reduced dose of cisplatin, ++P<0.05 when compared with Ad-NBS1/Reduced dose of cisplatin, *P<0.01 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin, **P<0.05 when compared with FGF2-Ad-NBS1/Reduced dose of cisplatin.
Mentions: The benefit of FGF2-targeted adenoviral system in tumour suppression was investigated using the MTT assay. JHU006 cells were subjected to six interventions. The cell growth in Ad-NBS1/cisplatin and FGF2-Ad-NBS1/cisplatin had a greater inhibition than that in other groups at an MOI of 5 (Figure 3A). The cell growth of Ad-NBS1/cisplatin and FGF2-Ad-NBS1/cisplatin also had a greater inhibition than that of the Control or Cisplatin groups at an MOI of 10 (Figure 3B); however, no difference was observed when compared with that of Ad-NBS1 or FGF2-Ad-NBS1. These results at an MOI of 5 show that the tumour inhibition in FGF2-Ad-NBS1/cisplatin has more effect at an early phase than that of Ad-NBS1/cisplatin. This is consistent with the results of the GFP expression in higher and earlier transduction of FGF2-Ad-NBS1/cisplatin than that of Ad-NBS1/cisplatin. However, the results at an MOI of 10 suggest that the transduction efficiency and tumour growth inhibition reaches the maximum level in Ad-NBS1/cisplatin at an MOI of 10. As a result, the FGF2-targeted system has the potential of a lower titre administration of virus while still achieving optimal cisplatin chemosensitisation effects.

Bottom Line: a fibroblast growth factor 2 (FGF2)-targeted adenoviral system can alter viral tropism and allow for improved transduction and reduced systemic toxicity.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.FGF2-targeted adenoviral system enhances the cisplatin chemosensitisation of mutant NBS1 and may avoid viral-associated liver toxicities.

View Article: PubMed Central - PubMed

Affiliation: Department of Otorhinolaryngology-Head & Neck Surgery, University of Pennsylvania School of Medicine, 415 Curie Boulevard, CRB Room 145, Philadelphia, PA 19104, USA.

Show MeSH
Related in: MedlinePlus