Lethality in an anti-angiogenic tumor gene therapy model upon constitutive but not inducible expression of the soluble vascular endothelial growth factor receptor 1

The Journal of Gene Medicine
Vijayshankar Ganesh SivanandamStefan Kochanek

Abstract

Neoangiogenesis is essential for tumor growth. The present study aimed to test the hypothesis that vector-mediated expression of sflt1 at high levels would result in the blockade of vascular endothelial growth factor (VEGF) function and therefore the inhibition of tumor growth. To sequester VEGF, we tested, in a subcutaneous LLC tumor model, 'gutless' high-capacity adenovirus vectors expressing the soluble VEGF receptor 1 (sflt1) in a liver-specific manner, either in a constitutive or in a RU486 induced manner. High serum levels of sflt1 were observed upon in vivo injection of both vectors. Despite the differences in expression kinetics, both modes of sflt1 expression resulted in significant though transient suppression of tumor growth. Unexpectedly, constitutive but not intermittent sflt1 expression resulted in ascites and death of all animals. Morphological analyses by light and electron microscopy indicated that the animals had died from a nephropathy, which apparently was due to the blockade of VEGF function. Although confirming earlier results of toxic effects of prolonged VEGF sequestration, the present study suggests that therapeutic anti-tumor effects can be achieved without side-effects with intermittent VEGF blockade ...Continue Reading

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Citations

Oct 29, 2010·International Journal of Hypertension·Sam L StephenSreenivasan Ponnambalam
Jul 23, 2011·Clinics and Research in Hepatology and Gastroenterology·Gloria Gonzalez-Aseguinolaza, Jesús Prieto
Jul 19, 2011·Cancer Treatment Reviews·Jordan Schmitt, Daniela Matei
Mar 23, 2017·Stroke; a Journal of Cerebral Circulation·Wan ZhuHua Su

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