title: Adeno-associated virus vector-mediated delivery of pigment epithelium-derived factor restricts neuroblastoma angiogenesis and growth.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the ability of adeno-associated virus (AAV) vector-mediated delivery of pigment epithelium-derived factor (PEDF) to inhibit neuroblastoma (NB) xenograft growth. Pigment epithelium-derived factor was chosen for this study because, in addition to being a potent inhibitor of angiogenesis, it is capable of inducing neuronal differentiation.
  
  
  METHODS
  Cohorts of mice received either recombinant AAV encoding human PEDF (rAAV-hPEDF) at a range of doses or control vector via tail vein. Subsequent hPEDF expression was measured by enzyme-linked immunoassay. After 6 weeks, the mice were given human NB cells by retroperitoneal injection and then killed 5 weeks later. Tumor weight, microvessel density, tumor differentiation, apoptosis, and levels of intratumoral vascular endothelial growth factor (VEGF) expression were determined at that time. In subsequent cohorts of mice, AAV-mediated murine PEDF expression was tested against both human NB xenografts and murine tumors.
  
  
  RESULTS
  In a series of in vitro studies, PEDF was shown to inhibit endothelial cell activation and to stimulate differentiation of NB cell lines. After tail vein injection of rAAV-hPEDF, stable transgene expression was generated and correlated with levels of vector administration. Human NB xenograft growth was restricted by hPEDF in a dose-dependent fashion. Intratumoral VEGF expression and microvessel density were decreased, and tumor cell apoptosis was increased in PEDF-treated mice.
  
  
  CONCLUSIONS
  Treatment with PEDF had a significant impact on NB growth in mice when delivered continuously using a gene therapy-mediated approach. The activity of PEDF appears to be mediated in part by inhibition of tumor-induced angiogenesis through down-regulation of tumor-elaborated VEGF, with subsequent intratumoral apoptosis. Furthermore, hPEDF was able to induce NB differentiation in vitro and in vivo. In addition, antitumor efficacy was seen when mouse PEDF was used to treat syngeneic murine tumors. In our murine models, gene therapy-mediated delivery of PEDF appears promising for the treatment of neuroblastoma.
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital and University of Tennessee-Memphis Health Science Center, Memphis, TN 38105, USA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Streck
authors.forename: Youbin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Junfang
authors.initials: J
authors.lastname: Zhou
authors.forename: Catherine
authors.initials: C
authors.lastname: Ng
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000229:Dependovirus; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000008:administration & dosage*; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D009447:Neuroblastoma / Q000628:therapy*; D009474:Neurons; D011480:Protease Inhibitors / Q000008:administration & dosage; D012186:Retroperitoneal Neoplasms / Q000628:therapy*; D015843:Serpins / Q000008:administration & dosage*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000970:Antineoplastic Agents; D005136:Eye Proteins; D009414:Nerve Growth Factors; D011480:Protease Inhibitors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor