Effective angiostatic treatment in a murine metastatic and orthotopic hepatoma model.
Vascular endothelial growth factor (VEGF) activity is correlated with a progressive tumor disease in patients with hepatocellular carcinoma (HCC). In spite of the well-recognized role of VEGF in HCC, there are few data available regarding therapeutic strategies to block VEGF activity. Therefore, we employed a recombinant adenoviral vector encoding a soluble dominant negative fragment of VEGF receptor 2 (Flk-1), AdsFlk-1, to control pre-established murine orthotopic and metastatic hepatomas. Vector function was confirmed via reverse-transcriptase polymerase chain reaction and ELISA, and angiostatic effects were analyzed in vitro and in vivo. Antitumoral effects of systemic AdsFlk-1 application were studied in a subcutaneous and orthotopic Hepa129 HCC model. Cell supernatant containing the truncated form of Flk-1 had no direct effect on cell proliferation of Hepa129 cells in vitro but reduced endothelial tube formation on matrigel matrix by approximately 80% in vitro. Endothelial-like cell infiltration into matrigel plugs in vivo was also decreased by 80%. Systemic treatment of tumor-bearing mice inhibited tumor growth by 84% compared with the corresponding control group within 16 days after vector application. Likewise, the survival rate was significantly improved in the AdsFlk-1 group compared with control. Orthotopic tumor growth was reduced by 82%, and development of malignant ascites was also retarded. In conclusion, systemic adenoviral-mediated gene transfer of an Flk-1 fragment significantly inhibited tumor growth in orthotopic and metastatic murine HCC. The data support the value of VEGF blockade as an effective target for HCC treatment.
Raskopf
Esther
E
Department of Internal Medicine I, University Hospital Bonn, Germany.
Dzienisowicz
Christian
C
Hilbert
Tobias
T
Rabe
Christian
C
Leifeld
Ludger
L
Wernert
Nicolas
N
Sauerbruch
Tilman
T
Prieto
Jesús
J
Qian
Cheng
C
Caselmann
Wolfgang H
WH
Schmitz
Volker
V
D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001973:Bromodeoxyuridine; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007797:Laminin; D008113:Liver Neoplasms / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics; D011509:Proteoglycans; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D010446:Peptide Fragments; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2; D001973:Bromodeoxyuridine