Soluble Flt-1 gene therapy for peritoneal metastases using HVJ-cationic liposomes

Mori, Akira; Arii, Shigeki; Furutani, Masaharu; Mizumoto, Masaki; Uchida, Satoshi; Furuyama, Hiroaki; Kondo, Yoko; Gorrin-Rivas, MJ; Furumoto, Katsuyoshi; Kaneda, Yasufumi; Imamura, Masayuki

doi:10.1038/sj.gt.3301202

Cited by 55 publications

(35 citation statements)

References 35 publications

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“…[11][12][13][14] In these studies, gene delivery with either Flk-1 or Flt-1 elicited a B80% suppression in tumor growth that was associated with decreased tumor microvessel density. 11 Similar antiangiogenic properties were demonstrated in the corneal micropocket assay in which Flk-1 and Flt-1 strongly inhibited corneal neovascularization.…”

Section: Discussionmentioning

confidence: 91%

“…Gene transfer with sFlt-1 or sFlk-1 markedly reduced tumor growth by inhibiting tumor angiogenesis in various animal tumor models. [11][12][13][14][15] Furthermore, in corneal micropocket assays in rodents, gene delivery significantly attenuated neovascularization induced by sustained release VEGF pellets. 11,16 Wound healing is a complex, dynamic process in which angiogenesis has been hypothesized to play an integral part since the formation of new blood vessels is a necessary step that allows a variety of mediators and regulators to reach the center of the healing process.…”

Section: Introductionmentioning

confidence: 99%

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Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

et al. 2004

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Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic (db/db) mice (each n¼20) received intravenous (i.v.) injections of recombinant adenoviruses (10 9 PFU) encoding the ligand-binding ectodomain of VEGF receptor 2 (Flk-1) or cDNA encoding the murine IgG2a Fc fragment (each n¼10). At 4 days after gene transfer, two full-thickness skin wounds (0.8 cm) were created on the dorsum of each animal. Wound closure was measured over 9-14 days after which wounds were resected for histological analysis. Prior to killing, fluorescent microspheres were systemically injected for quantitation of wound vascularity. Single i.v. injections of adenoviruses encoding soluble Flk-1 significantly decreased wound angiogenesis in both wild-type and diabetic mice. Fluorescence microscopy revealed a 2.0-fold (wild type) and 2.9-fold (diabetic) reduction in wound vascularity in Flk-1-treated animals (po0.05). Impairment of angiogenesis was confirmed by CD31 immunohistochemistry. Interestingly, despite significant reductions in wound vascularity, wound closure was not grossly delayed. Our data indicates that while VEGF function is essential for optimal wound angiogenesis, it is not required for wound closure.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

et al. 2004

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“…Treatment with sFlt-1, a naturally-occurring truncated and secreted form of VEGF receptor Flt-1, has been shown to inhibit angiogenesis in a variety of disease models. 29,30,35 The anti-angiogenic action of sFlt-1 is due to its ability to directly sequester VEGF and to form heterodimers with membrane-bound Flt-1 and VEGF receptor 2. 28,36 It is widely believed that VEGF up-regulation also plays a major part in the development of ocular NV.…”

Section: Discussionmentioning

confidence: 99%

Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy

et al. 2002

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“…The mortality associated with gastric cancer has remained relatively stable over the past 20 years, suggesting that new therapies to combat this problem are urgently needed (Karpeh et al, 2001). Recent studies have shown that targeting the tumour vasculature may be of therapeutic benefit in gastric cancer (Mori et al, 2000;Yoshikawa et al, 2000;Jung et al, 2002;Kamiyama et al, 2002).…”

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confidence: 99%

ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer

et al. 2004

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The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n ¼ 11 -12/group) received (a) vehicle, (b) ZD6126 at 100 mg kg day À1 i.p. one time per week or (c) ZD6126 at 100 mg kg day À1 i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg kg À1 mouse À1 or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (Po0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (Po0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (Po0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (Po 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (Po0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.

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Soluble Flt-1 gene therapy for peritoneal metastases using HVJ-cationic liposomes

Cited by 55 publications

References 35 publications

Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy

ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer

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