title: Lethality in an anti-angiogenic tumor gene therapy model upon constitutive but not inducible expression of the soluble vascular endothelial growth factor receptor 1.
abstract: 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.
authors: Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors: Vijayshankar Ganesh
authors: VG
authors: Sivanandam
authors: Sam Laurel
authors: SL
authors: Stephen
authors: Ruben
authors: R
authors: Hernandez-Alcoceba
authors: Pilar
authors: P
authors: Alzuguren
authors: Maider
authors: M
authors: Zabala
authors: Nico
authors: N
authors: van Rooijen
authors: Cheng
authors: C
authors: Qian
authors: Irina
authors: I
authors: Berger
authors: Marie-Luise
authors: ML
authors: Gross
authors: Jesus
authors: J
authors: Prieto
authors: Stefan
authors: S
authors: Kochanek
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1