Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in ... View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2003-01-01

AUTHORS

T Kanazawa, H Mizukami, T Okada, Y Hanazono, A Kume, H Nishino, K Takeuchi, K Kitamura, K Ichimura, K Ozawa

ABSTRACT

The application of adeno-associated virus (AAV) vectors to cancers is limited by their low transduction efficiency. Previously, we reported that γ-ray enhanced the second-strand synthesis, leading to the improvement of the transgene expression, and cytocidal effect of the herpes simplex virus type-1 thymidine kinase (HSVtk) and ganciclovir (GCV) system. In this study, we extended this in vitro findings to in vivo. First, the laryngeal cancer cell line (HEp-2) and HeLa were treated with AAVtk/GCV, the number of surviving cells was reduced as the concentration of GCV increased. Furthermore, the 4 Gy irradiation enhanced the killing effects of AAVtk/GCV by four-fold on HeLa cells and 15-fold on HEp-2 cells. Following the in vitro experiments, we evaluated the transgene expression and the antitumor activity of the AAV vectors in combination with γ-ray in nude mice inoculated with HEp-2 subcutaneously. The LacZ expression was observed in the xenografted tumors and significantly increased by γ-ray. The AAVtk/GCV system suppressed the tumors growth, and γ-ray augmented the antitumor activity by five-fold. These findings suggest that the combination of AAVtk/GCV system with radiotherapy is significantly effective in the treatment of cancers and may lead to reduction of the potential toxicity of both AAVtk/GCV and γ-ray. More... »

PAGES

51-58

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.gt.3301837

DOI

http://dx.doi.org/10.1038/sj.gt.3301837

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/12525837


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36 schema:description The application of adeno-associated virus (AAV) vectors to cancers is limited by their low transduction efficiency. Previously, we reported that γ-ray enhanced the second-strand synthesis, leading to the improvement of the transgene expression, and cytocidal effect of the herpes simplex virus type-1 thymidine kinase (HSVtk) and ganciclovir (GCV) system. In this study, we extended this in vitro findings to in vivo. First, the laryngeal cancer cell line (HEp-2) and HeLa were treated with AAVtk/GCV, the number of surviving cells was reduced as the concentration of GCV increased. Furthermore, the 4 Gy irradiation enhanced the killing effects of AAVtk/GCV by four-fold on HeLa cells and 15-fold on HEp-2 cells. Following the in vitro experiments, we evaluated the transgene expression and the antitumor activity of the AAV vectors in combination with γ-ray in nude mice inoculated with HEp-2 subcutaneously. The LacZ expression was observed in the xenografted tumors and significantly increased by γ-ray. The AAVtk/GCV system suppressed the tumors growth, and γ-ray augmented the antitumor activity by five-fold. These findings suggest that the combination of AAVtk/GCV system with radiotherapy is significantly effective in the treatment of cancers and may lead to reduction of the potential toxicity of both AAVtk/GCV and γ-ray.
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60 concentration
61 cytocidal effect
62 effect
63 efficiency
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65 expression
66 findings
67 five-fold
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69 ganciclovir
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71 gene therapy
72 growth
73 head
74 herpes simplex virus type 1 thymidine kinase
75 human head
76 improvement
77 irradiation
78 irradiation results
79 kinase
80 lacZ expression
81 laryngeal cancer cell line
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84 mice
85 neck cancer xenografts
86 nude mice
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94 simplex virus type 1 thymidine kinase
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96 suicide gene therapy
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