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Radiation-Mediated Up-Regulation of Gene Expression from Replication-Defective Adenoviral Vectors: Implications for Sodium Iodide Symporter Gene Therapy

Authors' Affiliations: ¹ Targeted Therapy Team, The Institute of Cancer Research; ² Centre for Molecular Oncology, Queen Mary's School of Medicine and Dentistry; ³ Head and Neck Unit, Royal Marsden Hospital, London, United Kingdom; ⁴ University of Surrey, Guildford, United Kingdom; ⁵ St. James's University Hospital, Leeds, United Kingdom; ⁶ Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota; and ⁷ INSERM, CHU Hôtel Dieu, Nantes, France

Requests for reprints: Kevin J. Harrington, Targeted Therapy Team, The Institute of Cancer Research, Chester Beatty Laboratories, Cancer Research U.K. Centre for Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, United Kingdom. Phone: 44-20-7153-5157; Fax: 44-20-7808-2235; E-mail: kevinh{at}icr.ac.uk.

Purpose: To assess the effects of external beam radiotherapy (EBRT) on adenoviral-mediated transgene expression in vitro and in vivo and to define an optimal strategy for combining sodium iodide symporter (NIS)–mediated ¹³¹I therapy with EBRT.

Experimental Design: Expression of reporter genes [NIS, green fluorescent protein (GFP), β-galactosidase (lacZ), and luciferase (Luc)] from replication-deficient adenoviruses was assessed in tumor cell lines under basal conditions and following irradiation. The effects of viral multiplicity of infection (MOI) and EBRT dose on the magnitude and duration of gene expression were determined. In vivo studies were done with Ad-CMV-GFP and Ad-RSV-Luc.

Results: EBRT increased NIS, GFP, and β-galactosidase expression in colorectal, head and neck, and lung cancer cells. Radiation dose and MOI were important determinants of response to EBRT, with greatest effects at higher EBRT doses and lower MOIs. Radiation exerted both transductional (through increased coxsackie-adenoviral receptor and integrin _v) and nontransductional effects, irrespective of promoter sequence (CMV, RSV, hTR, or hTERT). Analysis of the schedule of EBRT followed by viral infection revealed maximal transduction at 24 hours. Radiation maintained increasing radioiodide uptake from Ad-hTR-NIS over 6 days, in direct contrast to reducing levels in unirradiated cells. The effects of EBRT in increasing and maintaining adenovirus-mediated transgene expression were also seen in vivo using GFP- and luciferase-expressing adenoviral vectors.

Conclusions: Radiation increased the magnitude and duration of NIS gene expression from replication-deficient adenoviruses. The transductional effect is maximal at 24 hours, but radioiodide uptake is maintained at an elevated level over 6 days after infection.

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