Synthetic Arg-Gly-Asp-Ser analogues of the cell recognition site of fibronectin that retain antimetastatic and anti-cell adhesive properties.
Synthetic peptide analogues of the Arg-Gly-Asp-Ser (RGDS) sequence of fibronectin in which the amino acid of Gly was substituted with another one, named X, i.e. Arg-X-Asp-Ser (R-X-DS), and N-terminal modified R-X-DS have been synthesized to examine their antimetastatic effects in murine lung or liver metastasis models, as well as the inhibitory effect on tumor cell invasion, migration and adhesion in vitro. R-X-DS [X = Leu (L) or D-Leu (1)], as well as RGDS at a high dose of 3000 micrograms, significantly reduced the number of lung tumor colonies when they were co-injected with B16-BL6 melanoma. At a dose of 1000 micrograms/mouse, N-terminal modified R-X-DS, i.e. acetyl-D-R-X-DS [AcDR-X-DS: X = G, L or I], showed a more potent inhibitory effect on the lung or liver metastasis of B16-BL6 melanoma or L5178Y-ML25 lymphoma cells, respectively, as compared with RGDS or R-X-DS. AcDRLDS and AcDRIDS prevented the invasion of B16-BL6 cells into Matrigel/fibronectin- and Matrigel/laminin- coated filters, haptotactic migration, and the adhesion of the cells to both fibronectin- and laminin-coated substrates, whereas AcDRGDS inhibited only fibronectin-mediated cell functions. The intermittent i.v. administration of a water soluble vinylpolymer [poly(carboxyethylmethacrylamide), poly(CEMA)] containing R-X-DS (X = L or 1) or RGDS, following the subcutaneous inoculation of B16-BL6 cells, significantly inhibited spontaneous Jung metastasis as compared with multiple administrations of RGDS, R-X-DS or the untreated control.(ABSTRACT TRUNCATED AT 250 WORDS)
Komazawa
H
H
Institute of Immunological Science, Hokkaido University, Sapporo, Japan.
Saiki
I
I
Aoki
M
M
Kitaguchi
H
H
Satoh
H
H
Kojima
M
M
Ono
M
M
Itoh
I
I
Azuma
I
I
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D005260:Female; D005353:Fibronectins / Q000737:chemistry*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005353:Fibronectins; D009842:Oligopeptides; C046617:arginyl-glycyl-aspartyl-serine