1: Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1155-62. Epub 2007 Feb 2.

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

Sonveaux P, Frerart F, Bouzin C, Brouet A, Dewever J, Jordan BF, Gallez B, Feron
O.

Unit of Pharmacology and Therapeutics, Universite Catholique de Louvain Medical
School, Brussels, Belgium.

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.

PMID: 17276618 [PubMed - in process]

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