Irradiation promotes Akt-targeting therapeutic gene delivery to the tumor vasculature
| Autor: | Caroline Bouzin, Françoise Frérart, Pierre Sonveaux, Bernard Gallez, Agnès Brouet, Julie DeWever, Olivier Feron, Bénédicte F. Jordan |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Cancer Research Pathology medicine.medical_specialty Nitric Oxide Synthase Type III Angiogenesis Genetic enhancement Transgene Green Fluorescent Proteins Gene delivery Endothelial NOS Nitric Oxide Mice Liver Neoplasms Experimental Enos In vivo Neoplasms Medicine Animals Radiology Nuclear Medicine and imaging Enzyme Inhibitors Protein kinase B Radiation biology business.industry Gene Transfer Techniques Endothelial Cells Radiotherapy Dosage Genetic Therapy biology.organism_classification Combined Modality Therapy Vasodilation NG-Nitroarginine Methyl Ester Oncology Cancer research Endothelium Vascular Nitric Oxide Synthase business Proto-Oncogene Proteins c-akt |
| Zdroj: | International journal of radiation oncology, biology, physics. 67(4) |
| ISSN: | 0360-3016 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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