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  • Viral Transfer Technology
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A blood–tumor barrier limits gene transfer to experimental liver cancer: the effect of vasoactive compounds

Gene Therapy volume 7, pages 1824–1832 (2000)Cite this article

Abstract

We have evaluated gene transfer efficiency to tumor nodules in diethylnitrosoamine (DENA)-induced hepatocellular carcinoma (HCC) in rats using adenoviral vectors administered by three different routes: intraportal, intra-arterial and intratumoral injection. Our results showed that intraportal infusion could not transduce tumor nodules greater than 1 mm in diameter while the intra-arterial route allowed transduction of nodules up to 2–5 mm in diameter. Tumors greater than this size were resistant to transduction by intravascular route, but could be transduced by direct intratumoral injection, indicating that the obstacle preventing gene transfer to tumor cells was mainly at the level of tumor vasculature and not at the level of neoplastic cells. We have studied the extracellular matrix in tumoral lesions to assess whether nodules with different size and histological pattern have different profiles in relation to transduction efficacy. Immunohistochemical detection showed a high expression of fibronectin (FN), laminin (LN) and α-smooth muscle actin (α-SMA) in those large HCC, which were resistant to adenoviral infection. Intra-arterial infusion of vasoactive compounds (histamine, angiotensin II or nitric oxide donor nitroglycerin) before vector administration enhanced gene transfer to tumor nodules that were poorly transduced without pre-treatment. Nitroglycerin was active to enhance transduction of large tumors with trabecular or pseudoglandular histological pattern, which were impermeable to adenoviral vectors even after histamine or angiotensin treatments. Our data indicate the presence of a physical barrier between blood and neoplastic cells, which prevents transduction of the tumor by vectors given by the intravascular route. The thickness and impermeability of the barrier increases as the tumor nodule grows. Vasoactive compounds may be of value in gene therapy of liver cancer by increasing transduction efficiency by intravascularly administered vectors.

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Acknowledgements

We particularly thank Dr JL Lanciego for helpful advice in image processing and Dr Pilar Sesma for their helpful discussions We also thank Mertxe Fernández, Yolanda Azcona, Paula Garcés for their expert assistance. This work was supported in part by grant SAF 98–0146 of Consejo Interministerial de Ciencia y Tecnologa (CICYT) and by Inés Bemberg, J Vidal, Dr Cervera and M Mendez grants for Gene Therapy. RB is supported by Beca del Programa de Formación de Investigadores (Department of Education, Universities and Research of the Gobierno Vasco).

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  1. Department of Internal Medicine and Liver Unit, School of Medicine, University of Navarra, Pamplona, Spain

    R Bilbao, M Bustos, P Alzuguren, M Drozdzik, C Qian & J Prieto

  2. Department of Histology and Histopathology, School of Medicine, University of Navarra, Pamplona, Spain

    M J Pajares

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Bilbao, R., Bustos, M., Alzuguren, P. et al. A blood–tumor barrier limits gene transfer to experimental liver cancer: the effect of vasoactive compounds. Gene Ther 7, 1824–1832 (2000). https://doi.org/10.1038/sj.gt.3301312

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