Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites.
Malignant ascites is a common complication of advanced intraabdominal neoplasms for which standard treatments are suboptimal. Evidence suggests that tumor-mediated angiogenesis and enhanced vascular permeability in the peritoneal wall due to high levels of vascular endothelial growth factor play a fundamental role in the pathogenesis of malignant ascites. To explore the advantage of viral vector-mediated "targeted antiangiogenic therapy" in ascites formation, we constructed and administered adenoviral vectors encoding several different antiangiogenic proteins (angiostatin, endostatin, platelet factor 4, and a fusion protein between angiostatin and endostatin) alone or in combination intraperitoneally in mice with peritoneal carcinomatosis from breast cancer (TA3 cells) and ovarian cancer (SKOV-3 i.p. and ES-2 cell lines) to explore the potential of additive or synergistic activity. Our data demonstrated statistically significant downregulation of ascites formation, tumor growth, vascularity, and prolongation of animal survival after intraperitoneal treatment with antiangiogenic adenoviral vectors in three different ascites tumor models. Combined treatment proved to be more effective than treatment with one vector alone. Reduced ascites formation was accompanied by decreased microvascular density in the peritoneal wall and increased apoptosis of tumor cells after administration of antiangiogenic vectors in vivo. Of interest was the observation that AdPF4 caused a significant decrease in the level of VEGF secreted by tumor cells both in vitro and in TA3 ascites tumor-bearing animals in vivo. These data suggest that adenoviral vector-mediated delivery of genes encoding antiangiogenic proteins may represent a potentially new treatment modality for malignant ascites.
Hampl
M
M
Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurologic Disorder and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Tanaka
T
T
Albert
P S
PS
Lee
J
J
Ferrari
N
N
Fine
H A
HA
D000256:Adenoviridae / Q000235:genetics; D043168:Angiostatins; D000818:Animals; D017209:Apoptosis; D001201:Ascites / Q000628:therapy*; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000628:therapy; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D004396:Coloring Agents / Q000494:pharmacology; D015536:Down-Regulation; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000235:genetics; D004727:Endothelium / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics; D010957:Plasmids / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics; D010978:Platelet Factor 4 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004396:Coloring Agents; D043169:Endostatins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D010978:Platelet Factor 4; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen; C022616:thiazolyl blue