A NEW PSEUDO-PEPTIDE OF ARG-GLY-ASP (RGD) WITH INHIBITORY EFFECT ON TUMOR-METASTASIS AND ENZYMATIC DEGRADATION OF EXTRACELLULAR-MATRIX

A series of pseudo-peptide analogs of the Arg-Glp-Asp (RGD) sequence o f fibronectin have been synthesized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have b een examined. The partially modified retro pseudo-peptide of RGD, R-re v-COCH2CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (R-rev-COCH2CH2-D, FC-303) achiev ed more potent inhibition of lung metastasis of melanoma cells than FC -63, Among the analogs, FC-336, a p-xylylendiamine derivative having t wo FC-303 moieties, showed the most potent inhibitory effect on experi mental lung metastasis produced by i.v. co-injection with B16-BL6 mela noma or colon 26 M3.1. cells in a dose-dependent manner. Multiple admi nistrations of FC-336 after tumor inoculation also showed efficient th erapeutic potency against spontaneous lung metastasis of B16-BL6 melan oma in mice. Furthermore, FC-336 effectively inhibited the invasion, m igration and adhesion of tumor cells in vitro, but its inhibitory effe cts were not more than those of RGDS peptide. Zymography analysis reve aled that FC-336 inhibited the degradation of gelatin substrate by mat rix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indic ate that the pseudo-peptides of the RGD sequence, possessing the inhib itory property of the degradation by MMPs differently from original RG D-containing peptides, may be advantageous and useful in preventing tu mor metastasis.