Suppression of ovarian cancer by muscle-mediated expression of soluble VEGFR-1/Flt-1 using adeno-associated virus serotype 1-derived vector.
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.
Takei
Yuji
Y
Division of Genetics Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Mizukami
Hiroaki
H
Saga
Yasushi
Y
Yoshimura
Ichiro
I
Hasumi
Yoko
Y
Takayama
Takeshi
T
Kohno
Takahiro
T
Matsushita
Takashi
T
Okada
Takashi
T
Kume
Akihiro
A
Suzuki
Mitsuaki
M
Ozawa
Keiya
K
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
D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1