title: AAV-mediated persistent bevacizumab therapy suppresses tumor growth of ovarian cancer.
abstract: BACKGROUND
  Anti-angiogenesis therapies such as bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), have been used against ovarian cancer, but transient and low peritoneal drug levels are likely a factor in treatment failure. We hypothesized that a single administration of adeno-associated virus (AAV)-mediated intraperitoneal expression of bevacizumab would direct persistent expression and suppress growth and metastasis of ovarian cancer.
  
  
  METHODS
  AAVrh.10BevMab, a rhesus serotype 10 adeno-associated viral vector coding for bevacizumab, was evaluated for the capacity of a single intraperitoneal administration to persistently suppress peritoneal tumor growth in an intraperitoneal model of ovarian carcinomatosis with human ovarian cancer cells in nude immunodeficient mice.
  
  
  RESULTS
  The data demonstrates that AAVrh10.BevMab mediates persistent and high levels of bevacizumab in the peritoneal cavity following a single intraperitoneal administration in mice. In AAVrh10.BevMab treated A2780 human ovarian cancer-bearing mice, tumor growth was significantly suppressed (p<0.05) and the area of blood vessels in the tumor was decreased (p<0.04). Survival of mice with A2780 xenografts or SK-OV3 xenografts was greatly prolonged in the presence of AAVrh10.BevMab (p<0.001). Administration of AAVrh10.BevMab 4days after A2780-luciferase cell implantation reduced tumor growth (p<0.01) and increased mouse survival (p<0.0001). Combination of AAVrh10.BevMab with cytotoxic reagents paclitaxel or topotecan proved to be more effective in increasing survival than treatment with cytotoxic reagent alone.
  
  
  CONCLUSIONS
  A single administration of AAVrh10.BevMab provides sustained and high local expression of bevacizumab in the peritoneal cavity, and significantly suppresses peritoneal carcinomatosis and increases survival in an ovarian cancer murine model.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, United States.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Kaminsky
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, United States. Electronic address: geneticmedicine@med.cornell.edu.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College-Qatar, Doha, Qatar.
authors.forename: Arash
authors.initials: A
authors.lastname: Rafii
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000235:genetics*; D000068258:Bevacizumab; D002277:Carcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology*; D047368:Tumor Burden / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab
keywords: AAV vector; Anti-angiogenesis; Bevacizumab; Gene therapy; Ovarian cancer
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