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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1990 Jun-Jul;81(6-7):660–667. doi: 10.1111/j.1349-7006.1990.tb02624.x

Anti‐metastatic and Anti‐invasive Effects of Polymeric Arg‐Gly‐Asp (RGD) Peptide, Poly(RGD), and Its Analogues

Ikuo Saiki 1,✉, Jun Murata 1, Kazuhiko Matsuno 2, Ryu Ogawa 3, Norio Nishi 3, Seiichi Tokura 3, Ichiro Azuma 1
PMCID: PMC6504060  PMID: 2119367

Abstract

We have investigated the anti‐metastatic and anti‐invasive activities of polypeptide analogues based on the Arg‐Gly‐Asp (RGD) adhesive signal in fibronectin, poly(RGD), poly(RGDS)[Arg‐Gly‐Asp‐Ser] and poly(RGDT)[Arg‐Gly‐Asp‐Thr]. These polypeptides containing repetitive RGD sequences were able to inhibit experimental and spontaneous lung metastases of B16‐BL6 cells more effectively than the corresponding monomer peptides. In the spontaneous metastasis model, multiple i.v. administrations of these polymeric peptides before or after surgical excision of the primary tumor resulted in a significant reduction of lung tumor colonies. However, there was no significant difference in ability to inhibit spontaneous lung metastasis among poly(RGD), poly(RGDS) and poly(RGDT), although the carboxy‐terminal amino acid residue (i.e., Xaa in ‐RGDXaa‐) has been shown to play an important role in the expression of cell adhesive character. The treatment with poly(RGD) substantially prolonged the survival time for mice injected s.c. with B16‐BL6 melanoma as compared with the untreated control. We also found that the polypeptides were potently able to inhibit the invasion and migration of tumor cells in vitro. Since these polypeptide analogues showed no antigenicity in the host and had no toxic effect on tumor cells in vitro, they may be potentially useful in the prevention of cancer metastasis.

Keywords: RGD peptide, Tumor metastasis, Invasion, Haptotactic migration

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REFERENCES

  • 1. ) Fidler , I. J. The Ernst W. Bertner Memorial Award Lecture: The evolution of biological heterogeneity in metastatic neoplasms . In “ Cancer Invasion and Metastases: Biologic and Therapeutic Aspects ,” ed. Nicolson G. L. and Milas L. , pp. 5 – 26 ( 1984. ). Raven Press; , New York . [PubMed] [Google Scholar]
  • 2. ) Nicolson , G. L. Tumor cell instability, diversification, and progression to the metastatic phenotype: from oncofetal expression . Cancer Res. , 47 , 1473 – 1487 ( 1987. ). [PubMed] [Google Scholar]
  • 3. ) Hart , I. R. “ Seed and soil” revisited: mechanisms of site specific metastasis . Cancer Metastasis Rev. , 1 , 5 – 16 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Liotta , L. A. , Rao , C. V. and Barsky , S. H. Tumor invasion and the extracellular matrix . Lab. Invest. , 49 , 636 – 649 ( 1983. ). [PubMed] [Google Scholar]
  • 5. ) Terranova , V. P. , Hujanen , E. S. and Martin , G. R. Basement membrane and the invasive activity of metastatic tumor cells . J. Natl. Cancer Inst. , 77 , 311 – 316 ( 1986. ). [PubMed] [Google Scholar]
  • 6. ) McCarthy , J. B. and Furcht , L. T. Laminin and fibronectin promote the haptotactic migration of B16 mouse melanoma cells in vitro . J. Cell. Biol. , 98 , 1474 – 1480 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Kornblihtt , A. R. , Umezaka , K. , Vibe‐Pedrsan , K. and Baralle , F. E. Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene . EMBO J. , 4 , 1755 – 1759 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. ) Pierschbacher , M. D. and Ruoslahti , E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule . Nature , 309 , 30 – 33 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Ruoslahti , E. and Pierschbacher , M. D. Arg‐Gly‐Asp: a versatile cell recognition signal . Cell , 44 , 517 – 518 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Humphries , M. J. , Olden , K. and Yamada , K. M. A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells . Science , 233 , 467 – 470 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Humphries , M. J. , Yamada , K. M. and Olden , K. Investigation of the biological effects of anti‐cell adhesive synthetic peptides that inhibit experimental metastasis of B16‐F10 murine melanoma cells . J. Clin. Invest. , 81 , 782 – 790 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Saiki , I. , Iida , J. , Murata , J. , Ogawa , R. , Nishi , N. , Sugimura , K. , Tokura , S. and Azuma , I. Inhibition of the metastasis of murine malignant melanoma by synthetic polymeric peptides containing core sequence of cell‐adhesive molecules . Cancer Res. , 49 , 3815 – 3822 ( 1989. ). [PubMed] [Google Scholar]
  • 13. ) Saiki , I. , Murata , J. , Iida , J. , Nishi , N. , Sugimura , K. and Azuma , I. The inhibition of murine lung metastasis by synthetic polypeptides [poly(arg‐gly‐asp) and poly(tyr‐ile‐gly‐ser‐arg)] with a core sequence of cell adhesion molecules . Br. J. Cancer , 59 , 194 – 197 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Saiki , I. , Murata , J. , Iida , J. , Sakurai , T. , Nishi , N. , Matsuno , K. and Azuma , I. Antimetastatic effects of synthetic polypeptides containing repeated structures of the cell adhesive Arg‐Gly‐Asp (RGD) and Tyr‐Ile‐Gly‐Ser‐Arg (YIGSR) sequences . Br. J. Cancer , 60 , 722 – 728 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Pierschbacher , M. D. and Ruoslahti , E. Variants of the cell recognition site of fibronectin that retain attachment‐promoting activity . Proc. Natl. Acad. Sci. USA , 81 , 5985 – 5988 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Pierschbacher , M. D. and Ruoslahti , E. Influence of stereochemistry of the sequence Arg‐Gly‐Asp‐Xaa on binding specificity in cell adhesion . J. Biol. Chem. , 262 , 17294 – 17298 ( 1987. ). [PubMed] [Google Scholar]
  • 17. ) Murata , J. , Saiki , I. , Iida , J. , Azuma , I. , Kawahara , H. , Nishi , N. and Tokura , S. Inhibition of tumor cell adhesion by anti‐metastatic polypeptide containing a repetitive Arg‐Gly‐Asp sequence . Int. J. Biol. Macromol. , 11 , 226 – 232 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) McCarthy , J. B. , Palm , S. L. and Furcht , L. T. Migration of haptotaxis of a Schwann cell tumor line to the basement membrane glycoprotein laminin . J. Cell Biol. , 97 , 772 – 777 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Albini , A. , Iwamoto , Y. , Kleinman , H. K. , Martin , G. R. , Aaronson , S. A. , Kozlowski , J. M. and McEwan , R. N. A rapid in vitro assay for quantitating the invasive potential of tumor cells . Cancer Res. , 47 , 3239 – 3245 ( 1987. ). [PubMed] [Google Scholar]
  • 20. ) Saiki , I. , Murata , J. , Watanabe , K. , Fujii , J. , Abe , F. and Azuma , I. Inhibition of tumor cell invasion by ubenimex (bestatin) in vitro . Jpn. J. Cancer Res. , 80 , 873 – 878 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Gasic , G. J. , Gasic , T. B. , Galanti , N. , Johnson , T. and Murphy , S. Platelet tumor interactions in mice. The role of platelets in the spread of malignant disease . Int. J. Cancer , 11 , 704 – 718 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Jamieson , G. A. , Bastida , E. and Ordinas , A. Interaction of platelets and tumor cells . In “ Platelets in Biology and Pathology III ,” ed. MacIntyre D. E. and Gordon J. L. , pp. 161 – 189 ( 1987. ). Elsevier Science; , New York . [Google Scholar]
  • 23. ) Dedhar , S. , Ruoslahti , E. and Pierschbacher , M. D. A cell surface receptor complex for collagen type I recognizes the Arg‐Gly‐Asp sequence . J. Cell Biol. , 104 , 585 – 593 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Chelberg , M. K. , Tsilibery , E. C. , Hauses , A. R. and McCarthy , J. B. Type IV collagen‐mediated melanoma cell adhesion and migration: involvement of multiple, distinct domains of the collagen molecule . Cancer Res. , 49 , 4796 – 4802 ( 1989. ). [PubMed] [Google Scholar]
  • 25. ) Pearlstein , E. , Salk , P. L. , Yogeeswaran , G. and Karpatkin , S. Correlation between spontaneous metastatic potential, platelet‐aggregating activity of cell surface extracts, and cell surface sialylation in 10 metastatic‐variant derivatives of a rat renal sarcoma cell line . Proc. Natl. Acad. Sci. USA , 77 , 4336 – 4339 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Haverstick , D. M. , Cowan , J. F. , Yamada , K. M. and Santoro , S. A. Inhibition of platelet adhesion to fibronectin, fibrinogen, and von Willebrand factor substrates by a synthetic tetrapeptide derived from the cell‐binding domain of fibronectin . Blood , 66 , 946 – 952 ( 1985. ). [PubMed] [Google Scholar]
  • 27. ) Plow , E. P. , Pierschbacher , M. D. , Ruoslahti , E. , Marquerie , G. and Ginsberg , M. H. Arginyl‐glycyl‐aspartic acid sequences and fibrinogen binding to platelets . Blood , 70 , 110 – 115 ( 1987. ). [PubMed] [Google Scholar]

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