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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1993 Mar;84(3):326–335. doi: 10.1111/j.1349-7006.1993.tb02874.x

Antimetastatic Effect by Anti‐adhesion Therapy with Cell‐adhesive Peptide of Fibronectin in Combination with Anticancer Drugs

Ikuo Saiki 1,✉, Junya Yoneda 1, Hideo Kobayashi 1, Yu Igarashi 1, Hiroyuki Komazawa 1, Yukuo Ishizaki 2, Ikunoshin Kato 2, Ichiro Azuma 1
PMCID: PMC5919152  PMID: 8486531

Abstract

We have investigated the therapeutic effect of CH‐271 fusion polypeptide containing both cell‐binding domain (C‐274) and heparin‐binding domain (H‐271) of fibronectin in combination with anticancer drugs such as doxorubicin (DOX) or mitomycin C (MMC) on tumor metastasis of different types of tumors. CH‐271 fusion polypeptide alone significantly inhibited both liver and lung metastasis when it was co‐injected with L5178Y‐ML25 T‐lymphoma, RAW117‐H10 B‐lymphoma or B16‐BL6 melanoma cells, and spontaneous lung metastasis of B16‐BL6 melanoma cells when administered i.v. seven times before or after surgical excision of the primary tumors. Combined treatments with CH‐271 and either DOX or MMC significantly inhibited liver and lung metastasis of lymphoma or melanoma cells respectively, as compared with either treatment alone or the untreated control. Administrations of CH‐271 and DOX in combination substantially prolonged the survival time of mice injected i.v. with L5178Y‐ML25 cells. CH‐271 or DOX was effective for inhibiting the invasion of LS178Y‐ML25 cells into Matrigel in a concentration‐dependent manner. Our previous study has shown that CH‐271‐mediated inhibition of tumor invasion may be due in part to the anti‐cell adhesive property without affecting the cell growth, whereas the anti‐invasive effect of DOX was established to have resulted from the growth inhibition of tumor cells. Moreover, the combination of CH‐271 with DOX provided a more effective inhibition of tumor invasion into Matrigel than did either alone. Thus, we have demonstrated that the combination of anti‐cell adhesive CH‐271 and anticancer drugs such as DOX or MMC, i.e. anti‐adhesion therapy and chemotherapy, is a new approach that offers enhanced (additive) inhibitory effects on tumor metastasis and invasion.

Keywords: Metastasis, Recombinant fibronectin fragment, Anticancer drug, Combined therapy

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REFERENCES

  • 1. ) Fidler , I. J.The Ernst W. Bertner Memorial Award Lecture: the evolution of biological heterogeneity in metastatic nepolasmas . 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 , 331 – 316 ( 1986. ). [PubMed] [Google Scholar]
  • 6. ) McCarthy , J. B. and Furcht , L. T.Laminin and fibronectin promote the haptotactic migration of B16‐BL6 mouse melanoma cell in vitro . J. Cell Biol. , 98 , 1414 – 1480 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Karpathlan , S. and Pearlstein , E.Heterogenous mechanism of tumor cell‐induced platelet aggregation with possible strategy toward prevention of metastases . In “ Hemostasis Mechanisms and Metastasis ,” ed Honn K. V. and Sloane B. F. , pp. 139 – 169 ( 1984. ). Martinus Nijhorff; , Boston . [Google Scholar]
  • 8. ) Kornblihtt , A. R. , Umezaka , K. , Vibe‐Pedrsan , K. and Baralle , F. E.Primary structure of human fibronectin: differential splicing may generate least 10 polypeptides from a single gene . EMBO J. , 4 , 1755 – 1759 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Sasaki , M. , Kato , S. , Kohno , K. , Martin , G. R. and Yamada , Y.Sequence of the cDNA encoding the laminin B1 chain reveals a multidomain protein containing cysteine rich repeats . Proc. Natl. Acad. Sci. USA , 84 , 935 – 938 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Sasaki , M. and Yamada , Y.The laminin B2 chain has a multidomain structure homologous to the B1 chain . J. Biol. Chem. , 262 , 17111 – 17117 ( 1987. ). [PubMed] [Google Scholar]
  • 11. ) Suzuki , S. , Oldberg , A. , Hayman , E. G. , Pierschbacher , M. D. and Ruoslahti , E.Complete amino acid sequence of human vitronectin deduced from cDNA. Similarity of cell attachment sites in vitronectin and fibronectin . EMBO J. , 4 , 2519 – 2524 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) 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]
  • 13. ) Ruoslahti , E. and Pierschbacher , M. D.Arg‐Gly‐Asp: a versatile cell recognition signal . Cell , 44 , 517 – 518 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Graf , J. , Iwamoto , Y. , Sasaki , M. , Martin , G. R. , Kleinman , H. K. , Robey , F. A. and Yamada , Y.Identification of an amino acid sequence in laminin mediating cell attachment, chemotaxis, and receptor binding . Cell , 48 , 989 – 996 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) 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]
  • 16. ) 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 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Humphries , M. J. , Komoriya , A. , Akiyama , S. K. , Olden , K. and Yamada , K. M.Indentification of two distinct regions of the type III connecting segment of human plasma fibronectin that promote cell type‐specific adhesion . J. Biol. Chem. , 262 , 6886 – 6892 ( 1987. ). [PubMed] [Google Scholar]
  • 18. ) Saiki , I. , Murata , J. , Makabe , T. , Matsumoto , Y. , Ohdate , Y. , Kawase , Y. , Taguchi , Y. , Shimojo , T. , Kimizuka , F. , Kato , I. and Azuma , I.Inhibition of lung metastasis by synthetic and recombinant fragments of human fibronectin with functional domain . Jpn. J. Cancer Res. , 81 , 1003 – 1011 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) McCarthy , J. B. , Hagen , S. T. and Furcht , L. T.Human plasma fibronectin contains multiple adhesion‐ and motility‐promoting domains for metastatic melanoma cells . J. Cell Biol. , 102 , 179 – 188 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) McCarthy , J. B. , Skubitz , A. P. N. , Palm , S. L. and Furcht , L. T.Metastasis inhibition of different tumor types by purified laminin fragment and a heparin‐fragment of fibronectin . J. Natl. Cancer Inst. , 80 , 108 – 116 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Iwamoto , Y. , Robey , F. A. , Graf , J. , Sasaki , M. , Kleinman , H. K. , Yamada , Y. and Martin , G. R.YIGSR, a synthetic laminin pentapeptide, inhibits experimental metastasis formation . Science , 238 , 1132 – 1134 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Kumagai , H. , Tajima , M. , Ueno , Y. , Giga‐Hama , Y. and Ohba , M.Effect of cyclic RGD peptide on cell adhesion and tumor metastasis . Biochem. Biophys. Res. Commun. , 177 , 74 – 82 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Kleinman , H. K. , Graf , J. , Iwamoto , Y. , Sasaki , M. , Schasteen , C. S. , Yamada , Y. , Martin , G. R. and Robey , F. A.Identification of a second active site in laminin for promotion of cell adhesion and migration and inhibition of in vivo melanoma lung colonization . Arch. Biochem. Biophys. , 272 , 39 – 45 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Tressler , R. J. , Belloni , P. N. and Nicolson , G. L.Correlation of inhibition of adhesion of large lymphoma and hepatic sinusoidal endothelial cells by RGD‐containing peptide polymers with metastatic potential: role of integrin‐dependent and ‐independent adhesion mechanisms . Cancer Commun. , 1 , 55 – 63 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Saiki , I. , Iida , J. , Murata , J. , Ogwa , 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]
  • 26. ) Saiki , I. , Murata , 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]
  • 27. ) 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]
  • 28. ) Saiki , I. , Matsumoto , Y. , Murata , J. , Makabe , T. , Yoneda , J. , Okuyama , H. , Kimizuka , F. , Ishizaki , Y. , Kato , I. and Azuma , I.Recombinant fusion poly peptide with cell‐ and heparin‐binding domains of fibronectin inhibits liver metastasis of L‐5178Y‐ML25 lymphoma cells . Jpn. J. Cancer Res. , 82 , 1120 – 1129 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Matsumoto , Y. , Saiki , I. , Makabe , T. , Yoneda , J. , Murata , J. , Kimizuka , F. , Ishizaki , Y. , Kato , I. and Azuma , I.Inhibitory effect of antimetastatic fusion polypeptide of human fibronectin or tumor cell adhesion to extracellular matrices . Jpn. J. Cancer Res. , 82 , 1130 – 1138 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Hart , I. R.The selection and characterization of an invasive variant of the B16 melanoma . Am. J. Pathol. , 97 , 587 – 592 ( 1979. ). [PMC free article] [PubMed] [Google Scholar]
  • 31. ) Watanabe , Y. , Okura , A. , Naito , K. and Kobayashi , M.Murine liver metastasis model using L5178Y‐ML lymphoma and the effect of antitumor agents on the metastasis . Jpn. J. Cancer Res. , 79 , 1208 – 1216 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. ) Brunson , K. W. and Nicolson , G. L.Selection and biologic properties of malignant variants of a murine lymphosarcoma . J. Natl. Cancer Inst. , 61 , 1499 – 1503 ( 1978. ). [PubMed] [Google Scholar]
  • 33. ) Maki , M. , Takano , E. , Mori , H. , Sato , A. , Murachi , T. and Hatanaka , M.All four internally repetitive domains of pig calpastatin possess inhibitory activities against calpeins I and II . FEBS Lett. , 223 , 174 – 180 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Sekiguchi , K. , Klos , M. A. , Kurachi , K. , Yoshitake , S. and Hakomori , S.Human liver fibronectin complementary DNAs: identification of two different messenger RNAs possibly encoding the a and b subunits of plasma fibronectin . Biochemistry , 25 , 4936 – 4951 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Kimizuka , F. , Ohdate , Y. , Kawase , Y. , Shimojo , T. , Taguchi , Y. , Hashino , K. , Goto , S. , Hashi , H. , Kato , I. , Sekiguchi , K. and Titani , K.Role of type III homology repeats in cell adhesion function within the cell‐binding domain of fibronectin . J. Cell Biol. , 5 , 3045 – 3051 ( 1991. ). [PubMed] [Google Scholar]
  • 36. ) Saiki , I. , Murata , J. , Watanabe , K. , Fujii , H. , 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]
  • 37. ) Liotta , L. A. , Rao , C. N. and Wewer , U. M.Biochemical interaction of tumor cells with the basement membrane . Ann. Rev. Biochem. , 55 , 1037 – 1057 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Saiki , I. , Murata , J. , Makabe , T. , Nishi , N. , Tokura , S. and Azuma , I.Inhibition of tumor angiogenesis by a synthetic cell‐adhesive polypeptide containing the Arg‐Gly‐Asp (RGD) sequence of fibronectin, poly(RGD) . Jpn. J. Cancer Res. , 81 , 668 – 675 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. ) Barsky , S. H. , Rao , C. N. , Williams , J. E. and Liotta , L. A.Laminin molecular domains which alter metastasis in a murine model . J. Clin. Invest. , 74 , 843 – 848 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

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