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Inhibition of the Metastasis of Murine Malignant Melanoma by Synthetic Polymeric Peptides Containing Core Sequences of Cell-adhesive Molecules¹

Institute of Immunological Science [I. S., J. I., J. M., K. S., I. A.], and Department of Polymer Science, Faculty of Science [R. O., S. T., N. N.], Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060, Japan

We investigated that the antimetastatic and antiadhesive activities of peptides based on Arg-Gly-Asp adhesive signal in fibronectin could be augmented by their polymerization. Poly(Arg-Gly-Asp), which consists of a repetitive sequence of Arg-Gly-Asp, inhibited lung metastases in C57BL/6 mice more effectively than Arg-Gly-Asp tripeptide was able to do, when coinjected or separately injected with B16-BL6 cells. The adhesion of tumor cells to fibronectin was specifically inhibited by adding poly(Arg-Gly-Asp) but not unrelated peptides. In contrast, poly(Arg, Gly, Asp), in which three amino acids are randomly arranged, showed neither inhibition of lung metastases nor any adhesive ability to attach to tumor cells. The inhibitory effect of polymeric peptides containing the Arg-Gly-Asp sequence on lung metastases decreased according to the decreasing repeat units of the Arg-Gly-Asp core sequence. Polymeric peptides with Arg-Gly-Asp entrapped within the liposome membranes also caused a remarkable reduction of metastatic colonies. In a spontaneous metastasis model, multiple i.v. administrations of poly(Arg-Gly-Asp) after tumor inoculation caused the significant reduction of metastatic colonies in the lung but did not affect the growth (size) of primary tumor.

We found that the polymerization (multivalency) of the Arg-Gly-Asp core sequence was able to augment the inhibition of tumor lung metastases in experimental and spontaneous metastasis models as well as the cell-adhesive property more effectively than a monovalent unit of Arg-Gly-Asp peptide.

¹ This work was supported in part by Grants-in-Aid for Cancer Research from the Japanese Ministry of Education, Science and Culture; from the Japanese Ministry of Health and Welfare for Comprehensive 10-Year Strategy for Cancer Control; for Scientific Research and for Developmental Scientific Research (No. 62870023) from the Japanese Ministry of Education, Science and Culture; and for Scientific Research from the Japanese Ministry of Education, Science and Culture; by the Osaka Foundation for Promotion of Clinical Immunology; by Yamanouchi Foundation for Research on Metabolic Disorders; and by Grant-in-Aid for Special Project Research from Hokkaido University, Japan.

² To whom requests for reprints should be addressed.

Received 3/28/88. Revised 11/14/88. Revised 4/ 7/89. Accepted 4/19/89.

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