A novel enzyme/prodrug system for hypoxia- and radiation-regulated suicide gene therapy

Greco, O. and Scott, Simon D. and Tozer, G.M. and Marples, B. and Joiner, M.C. and Dachs, G.U. (2001) A novel enzyme/prodrug system for hypoxia- and radiation-regulated suicide gene therapy. In: Cancer Gene Therapy. Springer-Nature (doi:https://doi.org/10.1038/sj.cgt.7700412) (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)

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Official URL
http://dx.doi.org/10.1038/sj.cgt.7700412

Abstract

We have previously proposed the plant enzyme horseradish peroxidase ( HRP ) and the nontoxic plant hormone indole - 3 - acetic acid ( IAA ) as a novel enzyme/ prodrug combination for suicide gene therapy ( Greco et al. Cancer Gene Ther. 7: 1414, 2000 ). Compared with other widely used systems ( e.g. HSV TK/ GCV ), HRP/ IAA has the advantage of inducing tumour cell killing and a strong bystander effect not only in normoxia, but also in the tumour conditions of anoxia and hypoxia ( 0.1% O2 ). Here we demonstrate that HRP -mediated gene therapy can selectively enhance the tumoricidal action of ionising radiation. Incubation with IAA prior to or postX - rays induced an increase in sensitivity of HRP - expressing cells of 2.5 – 2.6 ( 0.1 mM IAA ) and 5.4 – 5.6 ( 0.5 mM IAA ). Delivery of the HRP gene itself or exposure of HRP ?cells to IAA did not affect the response to radiation. To specifically target the radio - and chemoresistant population in solid tumours, the HRP gene was placed under the control of hypoxia - or radiation - responsive promoters. Five copies of hypoxia - regulatory elements ( HREs ) from the PGK - 1 or the EPO genes were inserted upstream of the basal cytomegalovirus promoter. After 24 - h hypoxic incubation, the EPO and the PGK - 1 HREs induced a 30 – 40 - fold and a 5 – 6 - fold increase in HRP expression respectively. Transfection with the EPO - HRP construct conferred hypoxia - selective sensitivity to IAA and analogues. HRP production in irradiated cells was achieved by using radiation - responsive CArG elements (Marples et al. Gene Therapy. 7: 511, 2000 ). After 5 Gy X - irradiation, a selective 2 – 3 - fold increase in transgene expression was detected.

Item Type: Conference or workshop item (Proceeding)
Subjects: R Medicine
R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Simon Scott
Date Deposited: 03 Dec 2017 15:26 UTC
Last Modified: 05 Dec 2017 11:09 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/45888 (The current URI for this page, for reference purposes)
Scott, Simon D.: https://orcid.org/0000-0002-8290-0461
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