title: Suppression of ovarian cancer by muscle-mediated expression of soluble VEGFR-1/Flt-1 using adeno-associated virus serotype 1-derived vector.
abstract: Vascular endothelial growth factor (VEGF) is known to play a major role in angiogenesis in a variety of tumors. A soluble form of Flt-1 (sFlt-1), a VEGF receptor, is potentially useful as an antagonist of VEGF, and accumulating evidences suggest the applicability of sFlt-1 in tumor suppression by means of anti-angiogenesis. We previously demonstrated the efficacy of sflt-1 gene expression in situ to suppress tumor growth and ascites in ovarian cancer. Here, we demonstrate the therapeutic applicability of muscle-mediated expression of sFlt-1 in tumor-bearing mice. Initially, tumor suppressive action was confirmed by inoculating sFlt-1-expressing ovarian cancer (SHIN-3) cells into mice, both subcutaneously and intraperitoneally. To validate the therapeutic efficacy in a more clinically relevant model, adeno-associated virus vectors encoding sflt-1 were introduced into mouse skeletal muscles and were subsequently inoculated with tumor cells. As a result, high serum sFlt-1 levels were constantly observed, and the growth of both subcutaneously- and intraperitoneally-inoculated tumors was significantly suppressed. No delay in wound healing or adverse events of neuromuscular damage were noted, body weight did not change, and laboratory data, such as those representing liver and renal functions, were not affected. These results indicate that sFlt-1 suppresses growth and peritoneal dissemination of ovarian cancer by the inhibition of angiogenesis, and thus suggest the usefulness of gene therapy for ovarian cancer.
authors.affiliation: Division of Genetics Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takei
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saga
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yoshimura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hasumi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takayama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kohno
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kume
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000229:Dependovirus / Q000235:genetics; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy*; D013489:Suppression, Genetic; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1