Greco, O., Joiner, M.C., Doleh, A., Powell, A.D., Hillman, G. and Scott, S.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 (Print), 1476-5462 (Online) (doi:10.1038/sj.gt.3302640)

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Abstract

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
Uncontrolled Keywords:	HRE, CArG, HSVtk/GCV, glioma, breast cancer, GFP
Subjects:	R Medicine > RS Pharmacy and materia medica
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > Medway School of Pharmacy
Related URLs:	Publisher
Last Modified:	01 Nov 2016 10:45
URI:	http://gala.gre.ac.uk/id/eprint/8434

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