Effect of Anti-adhesion Therapy by a New Pseudo-peptide of Arg-Gly-Asp (RGD) on Tumor Metastasis

Yasuharu Ohnishi¹⁾³⁾, Hideki Fujii³⁾, Jun Murata³⁾, Takashi Sakamoto¹⁾, Kenji Tazawa²⁾, Masao Fujimaki¹⁾, Ikuo Saiki³⁾

Second Department of Surgery¹⁾, Department of Clinical Nursing²⁾, Faculty of Medicine, Department of Pathogenic Biochemistry³⁾, Research Institute for Wakan-yaku, Toyama Medical and Pharmaceutical University

In order to augment the inhibitory effect on tumor invasion and metastasis, we synthesized a new pseudo-peptide of RGD sequence (FC-336) and examined its inhibitory effect on tumor metastasis in vivo and on the adhesion, migration and invasion of tumor cells in vitro. FC-336 significantly inhibited experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma in a dose-dependent manner. The intraportal injection of FC-336 with colon 26-L5 cells, a highly liver-metastatic cell line of colon 26 carcinoma, resulted in marked suppression of metastatic colonies in the liver and reduction of the liver weight, whereas the co-injection of tumor cells with a high dose of RGDS led to slight inhibition of liver metastasis. Multiple i.v. injections of FC-336 after tumor inoculation or the co-injection of FC-336 with tumor cells caused significant inhibition of experimental liver metastasis. FC-336 significantly increased the survival rate for mice compared to untreated controls when co-injected intraportally with tumor cells or intravenously administered after tumor inoculation. Furthermore, FC-336 inhibited the invasion, migration and adhesion of tumor cells in vitro, but it was not more inhibitory than RGDS peptide. Zymographic analysis revealed that FC-336 inhibited the degradation of a gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while RGDS peptide did not affect the enzymatic degradation. These results indicate that the pseudo-peptides of RGD sequence, possessing the inhibitory property of degradation by MMPs differently from the original RGD-containing peptides, may provide an advantageous and useful basis for preventing tumor metastasis.

Key words
pseudo-peptide, metastasis, matrix metalloproteinase (MMP)

Reprint requests
Ikuo Saiki Department of Pathogenic Biochemistry, Research Institute for Wakan-Yaku, Toyama Medical and Pharmaceutical University 2630 Sugitani, Toyama, 930-0152 JAPAN

Accepted
December 3, 1997

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