VEGF receptor antisense therapy inhibits angiogenesis and peritoneal dissemination of human gastric cancer in nude mice.
The efficacy of a phosphorothioate antisense oligonucleotide (ASO) for KDR/Flk-1 (KDR/Flk-1-ASO), an endothelial cell-specific vascular endothelial growth factor (VEGF) receptor, was investigated on the peritoneal dissemination and angiogenesis of a human gastric cancer cell line in nude mice. Green fluorescent protein (GFP)-transduced NUGC-4 (NUGC-4-GFP) human gastric cancer cells were implanted into the peritoneal cavity of nude mice. KDR/Flk-1-ASO, -SO, or phosphate-buffered saline was administrated from days 7 to 14, 200 microg/mouse, once a day. The mice were sacrificed on day 28. Disseminated peritoneal tumor nodules expressing GFP were visualized by fluorescence microscopy. KDR/Flk-1-ASO significantly decreased the extent of peritoneal dissemination of the tumors. The number of cells undergoing apoptosis was significantly increased in the KDR/Flk-1-ASO-treated tumors. Microvessel density was significantly reduced in the KDR/Flk-1-ASO-treated tumor nodules. The KDR/Flk-1 antisense strategy, therefore, decreases tumor dissemination apparently by inhibiting angiogenesis.
Kamiyama
Masako
M
Department of Surgery II, Yokohama City University, School of Medicine, Yokohama, Japan.
Ichikawa
Yasushi
Y
Ishikawa
Takashi
T
Chishima
Takashi
T
Hasegawa
Satoshi
S
Hamaguchi
Yohei
Y
Nagashima
Yoji
Y
Miyagi
Yohei
Y
Mitsuhashi
Masato
M
Hyndman
David
D
Hoffman
Robert M
RM
Ohki
Shigeo
S
Shimada
Hiroshi
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049452:Green Fluorescent Proteins; D006801:Humans; D007124:Immunoenzyme Techniques; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010534:Peritoneal Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D011233:Precipitin Tests; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D040262:Receptors, Vascular Endothelial Growth Factor; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D013873:Thionucleotides; D014407:Tumor Cells, Cultured
D008164:Luminescent Proteins; D016376:Oligonucleotides, Antisense; D017978:Receptors, Growth Factor; D013873:Thionucleotides; D049452:Green Fluorescent Proteins; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor