ANTIMETASTATIC ACTIVITIES OF SYNTHETIC ARG-GLY-ASP-SER (RGDS) AND ARG-LEU-ASP-SER (RLDS) PEPTIDE ANALOGS 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 a dhesion to the components of extracellular matrix and basement membran e, and also tested the antimetastatic effect of their conjugates with trimesic acid, Ar(DRGDS)(3) and Ar(DRLDS)(3). AcDRGDS significantly in hibited tumor cell adhesion to fibronectin, vitronectin and RGDS subst rates, but not to CS1 substrate which is a ligand for the alpha(4) bet a(1) tumor surface integrin receptor, In contrast, AcDRLDS variant pep tide significantly inhibited tumor cell adhesion to laminin, in additi on to RGDS-mediated adhesion to fibronectin and vitronectin, AcDRLDS a lso inhibited tumor cell adhesion to CS1 as well as the RGDS sequence within the fibronectin molecule in a concentration-dependent manner, a lthough the inhibitory effect was less than that of the CS1 (EILDV) pe ptide, Ar(DRLDS)(3) inhibited the laminin- and fibronectin-mediated in vasion and migration of tumor cells, whereas Ar(DRGDS)(3) selectively inhibited fibronectin-mediated invasion and migration, Ar(DRGDS), and Ar(DRLDS)(3) were much more effective in inhibiting experimental lung or liver metastases of various types of murine and human tumors than t he original RGDS-containing peptides or Ar(COONa)(3). Multiple adminis trations of Ar(DRGDS)(3) or Ar(DRLDS)(3) potently inhibited spontaneou s lung metastasis produced by intra-footpad injection of B16-BL6 cells without affecting the primary tumor size at the time of surgical exci sion, as compared with RGDS peptide or untreated control. Thus, Ar(DRG DS)(3) and Ar(DRLDS)(3) substantially increased the exhibiting any ant imetastatic effect of the peptides without direct cytotoxicity.