Antimetastatic activities of synthetic Arg-Gly-Asp-Ser (RGDS) and Arg-Leu-Asp-Ser (RLDS) peptide analogues and their inhibitory mechanisms.
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 alpha 4 beta 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.
Fujii
H
H
Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University, Japan.
Komazawa
H
H
Mori
H
H
Kojima
M
M
Itoh
I
I
Murata
J
J
Azuma
I
I
Saiki
I
I
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009842:Oligopeptides; C098815:arginyl-leucyl-aspartyl-serine; C046617:arginyl-glycyl-aspartyl-serine