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Hypoxia- and radiation-activated Cre/loxP 'molecular switch' vectors for gene therapy of cancer.

Greco, Olga, Joiner, Michael C., Doleh, A., Powell, A.D., Hillman, G.G., Scott, Simon D. (2006) Hypoxia- and radiation-activated Cre/loxP 'molecular switch' vectors for gene therapy of cancer. Gene Therapy, 13 (3). pp. 206-215. ISSN 0969-7128. (doi:10.1038/ (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:82)

Language: English

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Although a significant negative prognostic factor, tumor hypoxia can be exploited for gene therapy. To maximize targeting within the tumor mass, we have developed synthetic gene promoters containing hypoxia-responsive elements (HREs) from the erythropoietin (Epo) gene as well as radiation-responsive CArG elements from the early growth response (Egr) 1 gene. Furthermore, to achieve high and sustained expression of the suicide gene herpes simplex virus thymidine kinase (HSVtk), our gene therapy vectors contain an expression amplification system, or 'molecular switch', based on Cre/loxP recombination. In human glioma and breast adenocarcinoma cells exposed to hypoxia and/or radiation, the HRE/CArG promoter rapidly activated Cre recombinase expression leading to selective and sustained HSVtk synthesis. Killing of transfected tumor cells was measured after incubation with the prodrug ganciclovir (GCV; converted by HSVtk into a cytotoxin). In vitro, higher and more selective GCV-mediated toxicity was achieved with the switch vectors, when compared with the same inducible promoters driving HSVtk expression directly. In tumor xenografts implanted in nude mice, the HRE/CArG-switch induced significant growth delay and tumor eradication. In conclusion, hypoxia- and radiation-activated 'molecular switch' vectors represent a promising strategy for both targeted and effective gene therapy of solid tumors.

Item Type: Article
DOI/Identification number: 10.1038/
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Susan Davies
Date Deposited: 19 Dec 2007 17:55 UTC
Last Modified: 16 Nov 2021 09:39 UTC
Resource URI: (The current URI for this page, for reference purposes)
Scott, Simon D.:
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