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

Naomi Chadderton, Rachel L. Cowen, Freda C D Sheppard, Suzanne Robinson, Olga Greco, Simon D. Scott, Ian J. Stratford, Adam V. Patterson, Kaye J. Williams

    Research output: Contribution to journalArticlepeer-review

    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% O2) 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-1α (HIF-1α) and HIF-2α 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-1α/2α 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 radio-resistant population at the time of radiation and also exploit microenvironmental changes after radiotherapy to yield additional switch-on. © 2005 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)213-222
    Number of pages9
    JournalInternational Journal of Radiation Oncology Biology Physics
    Volume62
    Issue number1
    DOIs
    Publication statusPublished - 1 May 2005

    Keywords

    • Enhancer
    • Genetic radiotherapy
    • HIF
    • Hypoxia
    • Radiation

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