Lethality in an anti-angiogenic tumor gene therapy model upon constitutive but not inducible expression of the soluble vascular endothelial growth factor receptor 1
Article first published online: 21 AUG 2008
Copyright © 2008 John Wiley & Sons, Ltd.
The Journal of Gene Medicine
Volume 10, Issue 10, pages 1083–1091, October 2008
How to Cite
Ganesh Sivanandam, V., Stephen, S. L., Hernandez-Alcoceba, R., Alzuguren, P., Zabala, M., van Rooijen, N., Qian, C., Berger, I., Gross, M.-L., Prieto, J. and Kochanek, S. (2008), Lethality in an anti-angiogenic tumor gene therapy model upon constitutive but not inducible expression of the soluble vascular endothelial growth factor receptor 1. J. Gene Med., 10: 1083–1091. doi: 10.1002/jgm.1244
- Issue published online: 5 SEP 2008
- Article first published online: 21 AUG 2008
- Manuscript Accepted: 11 JUL 2008
- Manuscript Received: 14 APR 2008
- German Research Foundation (DFG)
- Wilhelm Sander Foundation (to S.K.)
- adenovirus vector;
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 or the use of drugs with short half-lives, as shown by the use of an inducible gene expression system. Copyright © 2008 John Wiley & Sons, Ltd.