Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors: Implications for sodium iodide symporter gene therapy

Mohan Hingorani, Christine L. White, Shane Zaidi, Andrew Merron, Inge Peerlinck, Martin E. Gore, Christopher M. Nutting, Hardev S. Pandha, Alan A. Melcher, Richard Geoffrey Vile, Georges Vassaux, Kevin J. Harrington

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Abstract

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 131l 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 EBRTdoses and lower MOIs. Radiation exerted both transductional (through increased coxsackie-adenoviral receptor and integrin αv) 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.

Original languageEnglish (US)
Pages (from-to)4915
Number of pages1
JournalClinical Cancer Research
Volume14
Issue number15
DOIs
StatePublished - Aug 1 2008

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Gene Expression Regulation
Genetic Therapy
Up-Regulation
Radiotherapy
Radiation
Green Fluorescent Proteins
Luciferases
Adenoviridae
Galactosidases
Virus Diseases
Transgenes
Gene Expression
Head and Neck Neoplasms
Infection
sodium-iodide symporter
Tumor Cell Line
Reporter Genes
Integrins
Lung Neoplasms
Appointments and Schedules

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors : Implications for sodium iodide symporter gene therapy. / Hingorani, Mohan; White, Christine L.; Zaidi, Shane; Merron, Andrew; Peerlinck, Inge; Gore, Martin E.; Nutting, Christopher M.; Pandha, Hardev S.; Melcher, Alan A.; Vile, Richard Geoffrey; Vassaux, Georges; Harrington, Kevin J.

In: Clinical Cancer Research, Vol. 14, No. 15, 01.08.2008, p. 4915.

Research output: Contribution to journalArticle

Hingorani, M, White, CL, Zaidi, S, Merron, A, Peerlinck, I, Gore, ME, Nutting, CM, Pandha, HS, Melcher, AA, Vile, RG, Vassaux, G & Harrington, KJ 2008, 'Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors: Implications for sodium iodide symporter gene therapy', Clinical Cancer Research, vol. 14, no. 15, pp. 4915. https://doi.org/10.1158/1078-0432.CCR-07-4049
Hingorani, Mohan ; White, Christine L. ; Zaidi, Shane ; Merron, Andrew ; Peerlinck, Inge ; Gore, Martin E. ; Nutting, Christopher M. ; Pandha, Hardev S. ; Melcher, Alan A. ; Vile, Richard Geoffrey ; Vassaux, Georges ; Harrington, Kevin J. / Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors : Implications for sodium iodide symporter gene therapy. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 15. pp. 4915.
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abstract = "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 131l 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 EBRTdoses and lower MOIs. Radiation exerted both transductional (through increased coxsackie-adenoviral receptor and integrin αv) 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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T1 - Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors

T2 - Implications for sodium iodide symporter gene therapy

AU - Hingorani, Mohan

AU - White, Christine L.

AU - Zaidi, Shane

AU - Merron, Andrew

AU - Peerlinck, Inge

AU - Gore, Martin E.

AU - Nutting, Christopher M.

AU - Pandha, Hardev S.

AU - Melcher, Alan A.

AU - Vile, Richard Geoffrey

AU - Vassaux, Georges

AU - Harrington, Kevin J.

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N2 - 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 131l 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 EBRTdoses and lower MOIs. Radiation exerted both transductional (through increased coxsackie-adenoviral receptor and integrin αv) 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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