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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Sivanandam
Vijayshankar Ganesh
VG
Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Stephen
Sam Laurel
SL
Hernandez-Alcoceba
Ruben
R
Alzuguren
Pilar
P
Zabala
Maider
M
van Rooijen
Nico
N
Qian
Cheng
C
Berger
Irina
I
Gross
Marie-Luise
ML
Prieto
Jesus
J
Kochanek
Stefan
S
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy; D009389:Neovascularization, Pathologic; D014162:Transfection; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1