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Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth

Nature Medicine volume 3, pages 437–442 (1997)Cite this article

Abstract

Chronic systemic delivery of therapeutic proteins, such as inhibitors of angiogenesis, present a number of difficult pharmacological challenges. To overcome these problems for one such protein, we constructed retroviral and adenoviral vectors that express a novel, secretable form of the antiangiogenic protein, platelet factor 4 (sPF4). Vector-mediated sPF4 transduction selectively inhibits endothelial cell proliferation in vitro, and results in hypovascular tumors that grow slowly in vivo. Additionally, tumor-associated angiogenesis is inhibited and animal survival is prolonged, following transduction of established intracerebral gliomas by an sPF4-expressing adenoviral vector. These data support the concept that targeted antiangiogenesis, using virally mediated gene transfer, represents a promising strategy for delivering antiangiogenic therapy.

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References

  1. Folkman, J. Tumor angiogenesis: Therapeutic implications. New Engl. J. Med. 285, 1182–1186 (1971).

    Article  CAS  PubMed  Google Scholar 

  2. Brem, S., Cotran, R. & Folkman, J. Tumor angiogenesis: A quantitative method for histologic grading. J.Natl. Cancer Inst. 48, 347–356 (1972).

    CAS  PubMed  Google Scholar 

  3. Brem, S. The role of vascular proliferation in the growth of brain tumors. Clin. Neurosurg. 23, 440–453 (1976).

    Article  CAS  PubMed  Google Scholar 

  4. Maxwell, M. et al. Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cancer Res. 51, 1345–1351 (1991).

    CAS  PubMed  Google Scholar 

  5. Shweiki, D., Itin, A., Softer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Plate, K.H., Breier, G. Weich, H.A. & Risau, W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845–848 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. O'Reilly, M.S. et al. Angiostatin: A novel angiostatin inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Ingber, D. et al. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 348, 555–557 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. D'Amato, R.J., Loughnan, M.S., Flynn, E. & Folkman, J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. USA 91, 4082–4085 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maione, T.E. et al. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247, 77–79 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Maione, T.E., Gray, G.S., Hunt, A.J. & Sharpe, R.J. Inhibition of tumor growth in mice by an analogue of platelet factor 4 that lacks affinity for heparin and retains potent angiostatic activity. Cancer Res. 51, 2077–2083 (1991).

    CAS  PubMed  Google Scholar 

  12. Sharpe, R.J., Byers, H.R., Scott, C.F., Bauer, S.I. & Maione, T.E. Growth inhibition of murine melanoma and human colon carcinoma by recombinant human platelet factor 4. J. Natl. Cancer Inst. 82, 848–853 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. Staddon, A. & Bonnem, E. A randomized dose finding study of recombinant platelet factor 4 (rPF4) in cutaneous AIDS-related Kaposi's sarcoma (KS). Proc. Am. Soc. Clin. Oncol. 13, 3 (1994).

  14. O'Reilly, M.S., Holmgren, L., Chen, C. & Folkman, J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nature Med. 2, 689–692 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Millauer, B., Shawver, L.K., Plate, K.H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1mutant. Nature 367, 576–579 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Weinstat-Saslow, D.L., Zabrenetzky, V.S., Frazier, W.A., Roberts, D.D. & Steeg, P.S. Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma Cell line reduces primary tumor growth, metastatic potential and angiogenesis. Cancer Res. 54, 6504–6511 (1994).

    CAS  PubMed  Google Scholar 

  17. Millauer, B. et al. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types in vivo. Cancer Res. 56, 1615–1620 (1996).

    CAS  PubMed  Google Scholar 

  18. Rice, C.D. & Merchant, R.E. Systemic treatment with murine recombinant interleukin-1β inhibits the growth and progression of malignant glioma in the rat. J. Neuro-Oncol. 13, 43–55 (1992).

    Article  CAS  Google Scholar 

  19. Takamiya, Y., Brem, H., Ojeifo, J., Mineta, T. & Martuza, R.L. AGM-1470 inhibits the growth of human glioblastoma Cells in vitro and in vivo. Neurosurgery 34, 869–875 (1994).

    CAS  PubMed  Google Scholar 

  20. Holmgren, L., O'Reilly, M.S. & Folkman, J. Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1, 149–153 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Alon, T. et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Med. 1, 1024–1028 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Hamada, J., Cavanaugh, P.G., Lotan, O. & Nicolson, G.L. Separable growth and migration factors for large Cell lymphoma Cells secreted by microvascular endothelial Cells derived from target organs for metastasis. Br. J. Cancer 66, 349–354 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Graeber, G.G. et al. Hypoxia-mediated selection of Cells with diminished apoptotic potential in solid tumors. Nature 379, 88–91 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Fine, H.A. Prospects for gene therapy as an innovative approach to malignant gliomas. Perspect. Neural. Surg. 5, 115–127 (1994).

    Google Scholar 

  25. Chen, S.-H., Shine, H.D., Goodman, J.C. Grossman, R.G. & Woo, S.L.C. Gene therapy for brain tumor: Regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc. Natl. Acad. Sci. USA 91, 3054–3057 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dong, Y. et al. In vivo replication-deficient adenovirus vector-mediated transduction of the cytosine deaminase gene sensitizes glioma Cells to 5-fluorocytosine. Hum. Cene Ther. 7, 713–720 (1996).

    Article  CAS  Google Scholar 

  27. Hochberg, F.H. & Pruitt, A. Assumptions in the radiotherapy of glioblastomas. Neurology 30, 907–991 (1980).

    Article  CAS  PubMed  Google Scholar 

  28. McGrory, W.J., Bautista, D.S. & Graham, F.L. A simple technique for the rescue of early region 1 mutations into infectious human adenovirus type 5. Virology 163, 614–617 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Graham, F.L., Smiley, J., Russel, W.C., St Nairn, R. Characteristics of a human Cell line transformed by DNA from human adenovirus type 5. J. Gen. Virol. 36, 59–72 (1977).

    Article  CAS  PubMed  Google Scholar 

  30. Takamiya, Y., Friedlander, R.M., Brem, H., Malick, A. & Martuza, R.L. Inhibition of angiogenesis and growth of human nerve-sheath tumors by AGM-1470. J. Neurosurg. 78, 470–476 (1993).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Cancer Pharmacology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, 02115, USA

    Toshihide Tanaka, Yoshinobu Manome, Donald W. Kufe & Howard A. Fine

  2. Division of Neurology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, 02115, USA

    Patrick Wen

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  1. Toshihide Tanaka
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  4. Donald W. Kufe
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Tanaka, T., Manome, Y., Wen, P. et al. Viral vector-mediated transduction of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth. Nat Med 3, 437–442 (1997). https://doi.org/10.1038/nm0497-437

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