Antimetastatic Activities of Synthetic Arg-Gly-Asp-Ser (RGDS) and Arg-Leu-Asp-Ser (RLDS) Peptide Analogues and Their Inhibitory Mechanisms
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概要
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We have investigated the inhibitory effect of the N-terminal modified Arg-Gly-Asp-Ser (RGDS) analogues, AcDRGDS and AcDRLDS, on tumor cell adhesion to the components of extracellular matrix and basement membrane, and also tested the antimetastatic effect of their conjugates with trimesic acid, Ar (DRGDS)_3 and Ar (DRLDS)_3. AcDRGDS significantly inhibited tumor cell adhesion to fibronectin, vitronectin and RGDS substrates, but not to CS1 substrate which is a ligand for the α_4β_1 tumor surface integrin receptor. In contrast, AcDRLDS variant peptide significantly inhibited tumor cell adhesion to laminin, in addition to RGDS-mediated adhesion to fibronectin and vitronectin. AcDRLDS also inhibited tumor cell adhesion to CS1 as well as the RGDS sequence within the fibronectin molecule in a concentration-dependent manner, although the inhibitory effect was less than that of the CS1 (EILDV) peptide. Ar (DRLDS)_3 inhibited the laminin- and fibronectin-mediated invasion and migration of tumor cells, whereas Ar (DRGDS)_3 selectively inhibited fibronectin-mediated invasion and migration. Ar (DRGDS)_3 and Ar (DRLDS)_3 were much more effective in inhibiting experimental lung or liver metastases of various types of murine and human tumors than the original RGDS-containing peptides or Ar (COONa)_3. Multiple administrations of Ar (DRGDS)_3 or Ar (DRLDS)_3 potently inhibited spontaneous lung metastasis produced by intra-footpad injection of B16-BL6 cells without affecting the primary tumor size at the time of surgical excision, as compared with RGDS peptide or untreated control. Thus, Ar (DRGDS)_3 and Ar (DRLDS)_3 substantially increased the exhibiting any antimetastatic effect of the peptides without direct cytotoxicity.
- 社団法人日本薬学会の論文
- 1995-12-15
著者
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済木 育夫
Research Institute For Wakan-yaku Toyama Medical And Pharmaceutical University
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済木 育夫
富山医科薬科大学 和漢薬研究所 病態生化学
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伊藤 勇
富士写真フイルム(株)足柄研究所
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藤猪 英樹
富山医薬大・和漢研・病態生化学
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藤猪 英樹
Research Institute for Wakan-Yaku (Traditional Sino-Japanese Medicines), Toyama Medical and Pharmace
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駒澤 宏幸
Fuji Photo Film Co., Ltd., Ashigara Research Laboratories
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森 秀登
Fuji Photo Film Co., Ltd., Ashigara Research Laboratories
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小島 政芳
Fuji Photo Film Co., Ltd., Ashigara Research Laboratories
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伊藤 勇
Fuji Photo Film Co., Ltd., Ashigara Research Laboratories
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村田 純
Research Institute for Wakan-Yaku (Traditional Sino-Japanese Medicines), Toyama Medical and Pharmace
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東 市郎
Institute of Immunological Science, Hokkaido University
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駒澤 宏幸
Fuji Photo Film Co. Ltd. Ashigara Research Laboratories
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東 市郎
函館工業高等専門学校
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小島 政芳
Fuji Photo Film Co. Ltd. Ashigara Research Laboratories
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森 秀登
Fuji Photo Film Co. Ltd. Ashigara Research Laboratories
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剤木 育夫
富山医科薬科大学医学部和漢薬研究所病態生化学部門
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Kojima Masami
Central Research Laboratory Kissei Pharmaceutical
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Azuma I
Institute Of Immunological Science Hokkaido University
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Saiki I
Toyama Medical And Pharmaceutical Univ. Toyama Jpn
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伊藤 勇
富士写真フィルム株式会社足柄研究所
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Itoh I
Fuji Photo Film Co. Ltd. Ashigara Research Laboratories
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Azuma I
Hakodate National College Of Technology
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Kojima M
Tokyo Pharmaceutical Research Center Pharmaceutical Technology Research Laboratories Daiichi Pharmac
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済木 育夫
富山医科薬科大学和漢薬研病態生化学部門
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