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Dual responsive promoters to target therapeutic gene expression to radiation-resistant hypoxic tumor cells

Chadderton, Naomi, Cowen, Rachel L., Sheppard, Freda C.D., Robinson, Suzanne, Greco, Olga, Scott, Simon D., Stratford, Ian J., Patterson, Adam V., Williams, Kaye J. (2005) Dual responsive promoters to target therapeutic gene expression to radiation-resistant hypoxic tumor cells. International Journal of Radiation Oncology Biology Physics, 62 (1). pp. 213-222. ISSN 0360-3016. (doi:10.1016/j.ijrobp.2005.01.031) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:9639)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided.
Official URL:
http://dx.doi.org/10.1016/j.ijrobp.2005.01.031

Abstract

Purpose: Tumor hypoxia is unequivocally linked to poor radiotherapy outcome. This study aimed to identify enhancer sequences that respond maximally to a combination of radiation and hypoxia for use in genetic radiotherapy approaches. Methods and Materials: The influence of radiation (5 Gy) and hypoxia (1% O-2) on reporter-gene expression driven by hypoxia (HRE) and radiation (Egr-1) responsive elements was evaluated in tumor cells grown as monolayers or multicellular spheroids. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-2 alpha protein expression was monitored in parallel. Results: Of the sequences tested, an HRE from the phosphoglycerate kinase-1 gene (PGK-18[5+]) was maximally induced in response to hypoxia plus radiation in all 5 cell lines tested. The additional radiation treatment afforded a significant increase in the induction of PGK-18[5+] compared with hypoxia alone in 3 cell lines. HIF-1 alpha/2 alpha were induced by radiation but combined hypoxia/radiation treatment did not yield a further increase. The dual responsive nature of HREs was maintained when spheroids were irradiated after delivery of HRE constructs in a replication-deficient adenovirus. Conclusions: Hypoxia-responsive enhancer element sequences are dually responsive to combined radiation and hypoxic treatment. Their use in genetic radiotherapy in vivo could maximize expression in the most radioresistant population at the time of radiation and also exploit microenvironmental changes after radiotherapy to yield additional switch-on.

Item Type: Article
DOI/Identification number: 10.1016/j.ijrobp.2005.01.031
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Simon Scott
Date Deposited: 13 Sep 2008 18:55 UTC
Last Modified: 16 Nov 2021 09:48 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/9639 (The current URI for this page, for reference purposes)

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