INHIBITION OF TUMOR INVASION AND METASTASIS BY PEPTIDIC MIMETICS OF ARG-GLY ASP (RGD) DERIVED FROM THE CELL RECOGNITION SITE OF FIBRONECTIN

The partially modified retro- and retro-inverso peptides of the Arg-Gl y Asp (RGD) sequence of fibronectin, in which the direction of the Arg residue is reversed and/or the chirality of the amino acid residue is inverted, i.e.,mainly R(rev)-COCH2CO-D and (D)R(rev)-COCH2CO-D, have been synthesized to examine their antimetastatic effects in murine lun g or liver metastasis models, as well as their inhibitory effect on tu mor cell invasion in vitro. R(rev)-COCH2CO-D inhibited lung metastasis produced by IV coinjection with B16-BL6 melanoma more potently than d id other pseudo-peptides or the original RGDS peptide. R(rev)-COCH2CO- D also showed antimetastatic effects against several different types o f tumor cells such as B16-BL6 melanoma, Colon26 M3.1 carcinoma, and L5 178Y-ML25 lymphoma cells, in a dose-dependent manner, and multiple adm inistrations had a therapeutic effect on spontaneous lung metastasis. The invasion of melanoma cells into reconstituted basement membrane Ma trigel in vitro was suppressed by R(rev)-COCH2CO-D more effectively th an by RGDS. These results indicate that the antimetastatic effect by R (rev)-COCH2CO-D was in part due to the inhibition of tumor invasion. T he RGDS peptide decomposed when incubated with fresh plasma in vitro, whereas R(rev)-COCH2CO-D was not affected by this treatment. Thus, the reversion of the Arg-Gly linkage in the RGD sequence resulted in prot ease resistance leading to the retardation of the clearance of the pep tide in vivo, and consequently augmented its antimetastatic and antiin vasive properties. Designed peptide analogues may provide various adva ntages and be useful for preventing cancer metastasis. Copyright (C) 1 996 Elsevier Science Inc.