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Title: Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature

Abstract

Purpose: To determine whether radiation-induced increases in nitric oxide (NO) production can influence tumor blood flow and improve delivery of Akt-targeting therapeutic DNA lipocomplexes to the tumor. Methods and Materials: The contribution of NO to the endothelial response to radiation was identified using NO synthase (NOS) inhibitors and endothelial NOS (eNOS)-deficient mice. Reporter-encoding plasmids complexed with cationic lipids were used to document the tumor vascular specificity and the efficacy of in vivo lipofection after irradiation. A dominant-negative Akt gene construct was used to evaluate the facilitating effects of radiotherapy on the therapeutic transgene delivery. Results: The abundance of eNOS protein was increased in both irradiated tumor microvessels and endothelial cells, leading to a stimulation of NO release and an associated increase in tumor blood flow. Transgene expression was subsequently improved in the irradiated vs. nonirradiated tumor vasculature. This effect was not apparent in eNOS-deficient mice and could not be reproduced in irradiated cultured endothelial cells. Finally, we combined low-dose radiotherapy with a dominant-negative Akt gene construct and documented synergistic antitumor effects. Conclusions: This study offers a new rationale to combine radiotherapy with gene therapy, by directly exploiting the stimulatory effects of radiation on NO production by tumor endothelial cells. Themore » preferential expression of the transgene in the tumor microvasculature underscores the potential of such an adjuvant strategy to limit the angiogenic response of irradiated tumors.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3]
  1. Unit of Pharmacology and Therapeutics, Universite Catholique de Louvain Medical School, Brussels (Belgium)
  2. Unit of Biomedical Resonance Imaging, Universite Catholique de Louvain Medical School, Brussels (Belgium)
  3. Unit of Pharmacology and Therapeutics, Universite Catholique de Louvain Medical School, Brussels (Belgium). E-mail: feron@mint.ucl.ac.be
Publication Date:
OSTI Identifier:
20944775
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 67; Journal Issue: 4; Other Information: DOI: 10.1016/j.ijrobp.2006.11.031; PII: S0360-3016(06)03506-1; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BLOOD FLOW; DNA; GENE THERAPY; GENES; IN VIVO; IRRADIATION; LIPIDS; NEOPLASMS; PLASMIDS; PROTEINS; RADIATION DOSES; RADIOTHERAPY; SPECIFICITY; STIMULATION; VASODILATION

Citation Formats

Sonveaux, Pierre, Frerart, Francoise, Bouzin, Caroline, Brouet, Agnes, Wever, Julie de, Jordan, Benedicte F., Gallez, Bernard, and Feron, Olivier. Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2006.11.031.
Sonveaux, Pierre, Frerart, Francoise, Bouzin, Caroline, Brouet, Agnes, Wever, Julie de, Jordan, Benedicte F., Gallez, Bernard, & Feron, Olivier. Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature. United States. doi:10.1016/j.ijrobp.2006.11.031.
Sonveaux, Pierre, Frerart, Francoise, Bouzin, Caroline, Brouet, Agnes, Wever, Julie de, Jordan, Benedicte F., Gallez, Bernard, and Feron, Olivier. Thu . "Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature". United States. doi:10.1016/j.ijrobp.2006.11.031.
@article{osti_20944775,
title = {Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature},
author = {Sonveaux, Pierre and Frerart, Francoise and Bouzin, Caroline and Brouet, Agnes and Wever, Julie de and Jordan, Benedicte F. and Gallez, Bernard and Feron, Olivier},
abstractNote = {Purpose: To determine whether radiation-induced increases in nitric oxide (NO) production can influence tumor blood flow and improve delivery of Akt-targeting therapeutic DNA lipocomplexes to the tumor. Methods and Materials: The contribution of NO to the endothelial response to radiation was identified using NO synthase (NOS) inhibitors and endothelial NOS (eNOS)-deficient mice. Reporter-encoding plasmids complexed with cationic lipids were used to document the tumor vascular specificity and the efficacy of in vivo lipofection after irradiation. A dominant-negative Akt gene construct was used to evaluate the facilitating effects of radiotherapy on the therapeutic transgene delivery. Results: The abundance of eNOS protein was increased in both irradiated tumor microvessels and endothelial cells, leading to a stimulation of NO release and an associated increase in tumor blood flow. Transgene expression was subsequently improved in the irradiated vs. nonirradiated tumor vasculature. This effect was not apparent in eNOS-deficient mice and could not be reproduced in irradiated cultured endothelial cells. Finally, we combined low-dose radiotherapy with a dominant-negative Akt gene construct and documented synergistic antitumor effects. Conclusions: This study offers a new rationale to combine radiotherapy with gene therapy, by directly exploiting the stimulatory effects of radiation on NO production by tumor endothelial cells. The preferential expression of the transgene in the tumor microvasculature underscores the potential of such an adjuvant strategy to limit the angiogenic response of irradiated tumors.},
doi = {10.1016/j.ijrobp.2006.11.031},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 4,
volume = 67,
place = {United States},
year = {Thu Mar 15 00:00:00 EDT 2007},
month = {Thu Mar 15 00:00:00 EDT 2007}
}