Synthetic Arg-Gly-Asp-Ser Analogues of the Cell Recognition Site of Fibronectin That Retain Antimetastatic and Anti-cell Adhesive Properties
| Autor: | Mitsunori Ono, Ikuo Saiki, Miho Aoki, Isamu Itoh, Ichiro Azuma, Hiroyuki Komazawa, Masayoshi Kojima, Hideaki Satoh, Hiroshi Kitaguchi |
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| Rok vydání: | 1993 |
| Předmět: |
Pathology
medicine.medical_specialty Molecular Sequence Data Cell Melanoma Experimental Pharmaceutical Science Antineoplastic Agents Mice Structure-Activity Relationship In vivo Laminin Antimetastatic Agent Cell Adhesion medicine Animals Amino Acid Sequence Neoplasm Metastasis Pharmacology Mice Inbred BALB C Matrigel biology Melanoma General Medicine medicine.disease Molecular biology In vitro Fibronectins Mice Inbred C57BL Fibronectin medicine.anatomical_structure Mice Inbred DBA biology.protein Female Oligopeptides |
| Zdroj: | Biological and Pharmaceutical Bulletin. 16:997-1003 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.16.997 |
| Popis: | 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 μg, significantly reduced the number of lung tumor colonies when they were co-injected with B16-BL6 melanoma. At a dose of 1000 μg/mouse, N-terminal modified R-X-DS, i.e. acetyl-D-R-X-DS [AcDR-X-DS : X=G, L or l], 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 AcDRlDS 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 l) or RGDS, following the subcutaneous inoculation of B16-BL6 cells, significantly inhibited spontaneous lung metastasis as compared with multiple administrations of RGDS, R-X-DS or the untreated control. These results indicate that synthetic AcDR-X-DS (X=G, L or l) analogues and poly(CEMA-R-X-DS) conjugates may be useful for preventing cancer metastasis. It is of great interest that AcDR-X-DS (X=L or l) was able to regulate tumor cell adhesion, migration and invasion mediated by laminin as well as by fibronectin differently than AcDRGDS. |
| Databáze: | OpenAIRE |
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