title: Combined endostatin/sFlt-1 antiangiogenic gene therapy is highly effective in a rat model of HCC.
abstract: Hepatocellular carcinoma (HCC) is regarded as a suitable target for antiangiogenic strategies. However, antiangiogenic agents aimed at single targets can be neutralized by upregulation of other proangiogenic factors. Therefore, combined approaches addressing at least two angiogenic targets should be more effective. Employing an appropriate rat hepatoma model, we examined the effects of sFlt-1 (soluble vascular endothelial growth factor [VEGF] receptor 1 as an indirect inhibitor of angiogenesis) and endostatin (a direct inhibitor of angiogenesis) in both single-agent as well as combined approaches under in vitro and in vivo conditions. Similar to human HCC, rat Morris hepatoma (MH) cells secreted high levels of VEGF, but no endogenous sFlt-1. Parental MH or MHES(r) cells, stably expressing rat endostatin, were adenovirally transduced either with AdsFlt-1 (encoding sFlt-1) or control vector Adnull (containing no transgene), followed by subcutaneous inoculation into syngeneic ACI rats. Compared with MH/Adnull cells, expressing no antiangiogenic factors at all, tumor weights were reduced fourfold in the MHES(r)/Adnull group, 19-fold in the MH/AdsFlt-1-group, and 77-fold in the MHES(r)/AdsFlt-1 combination therapy group. Analysis of variance did not show a significant interaction between the effects of the two factors ES(r) and sFlt-1; their effects multiplied. In conclusion, combined expression of sFlt-1 and endostatin effectively suppresses HCC growth under in vivo conditions. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
authors.affiliation: Department of Internal Medicine, University Clinic Tübingen, D-72076 Tübingen, Germany. florian.graepler@uni-tuebingen.de
authors.forename: Florian
authors.initials: F
authors.lastname: Graepler
authors.forename: Barbara
authors.initials: B
authors.lastname: Verbeek
authors.forename: Tilmann
authors.initials: T
authors.lastname: Graeter
authors.forename: Irina
authors.initials: I
authors.lastname: Smirnow
authors.forename: Hwai Loong
authors.initials: HL
authors.lastname: Kong
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Vonthein
authors.forename: Michael
authors.initials: M
authors.lastname: Gregor
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Lauer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D043169:Endostatins / Q000235:genetics*; D015316:Genetic Therapy; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology; D051381:Rats; D012995:Solubility; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D040281:Vascular Endothelial Growth Factor Receptor-1