Journal of Neuro-Oncology

, Volume 21, Issue 3, pp 189–201 | Cite as

Suramin inhibits glioma cell proliferationin vitro and in the brain

  • Shingo Takano
  • Stephen Gately
  • Herbert Engelhard
  • Ana Maria C. Tsanaclis
  • Steven Brem
Laboratory Investigation

Summary

Suramin is a novel anticancer agent that blocks the binding of growth factors, including basic fibroblast growth factor (bFGF), to their receptors. Prior studies showed human and experimental gliomas to upregulate and respond to autocrine stimulation by bFGF, the antiproliferative effects of suramin were therefore studied on glioma cell turnoverin vitro and in the brain. Suramin inhibited the growth of rat (C6,9L) and human (U-118, U-138, A-172, T98G) glioma cell lines in a dose-dependent manner. Suramin significantly reduced the bromodeoxyuridine (BUdR) labeling index of cultured glioma cells at 250 µg/ml, P < 0.0001. DNA flow cytometry revealed a significant decrease in the percentage of suramin-treated glioma cells in S-phase, P < 0.01. Using intracerebral rat C6 glioma modelin vivo, suramin, 10–60 mg/kg, i.p., produced a dose-dependent reduction of BUdR labeling in both the glioma and endothelial cell subpopulations. Suramin, 200 mg/kg i.V., however, led to intratumoral hemorrhages that reduced survival. Electron microscopy revealed membranous inclusion bodies in the cytoplasm of C6 glioma and endothelial cells, an indication of excess glycosaminoglycans. Moreover, 46% of endothelial cells within the C6 glioma tumor treated with suramin, 60 mg/kg, i.p., developed membrane blebs. Suramin, in clinically relevant doses, significantly inhibits glioma cell growth and cytokinetics. The risk of intratumoral hemorrhage, possibly related to injury of endothelial cells or the accumulation of anticoagulant glycosaminoglycans, constitutes a major side effect and caution should be exercised in consideration of clinical application for intracerebral tumors.

Key words

brain neoplasm bromodeoxyuridine flow cytometry glioma immunocytochemistry suramin 

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References

  1. 1.
    Stein CA, La Rocca RV, Thomas R, McAtee N, Myers CE: Suramin: An anticancer drug with unique mechanism of action. J Clin Oncol 7: 499–508, 1989PubMedGoogle Scholar
  2. 2.
    La Rocca RV, Stein CA, Myers CE: Suramin: Prototype of a new generation of antitumor compounds. Cancer Cells 2: 106–115, 1990PubMedGoogle Scholar
  3. 3.
    La Rocca RV, Stein CA, Danesi R, Jamis-Dow C, Weiss GH, Myers CE: Suramin in adrenal cancer: Modulation of steroid hormone production, cytotoxicityin vitro and clinical antitumor effect. J Clin Endocrinol Metab 71: 497–504, 1990PubMedGoogle Scholar
  4. 4.
    Myers CM, Cooper M, Stein C, La Rocca R, Walther MM, Weiss G, Choyke P, Dawson N, Steinberg S, Uhrich MM, Cassidy J, Kohler DR, Trepel J, Linehan DR: Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. J Clin Oncol 10: 881–889, 1992PubMedGoogle Scholar
  5. 5.
    Reed E, Cooper MR, La Rocca RV, Bostick-Bruton F, Myers CE: Suramin in advanced platinum-resistant ovarian cancer. Eur J Cancer 28A: 864–866, 1992PubMedGoogle Scholar
  6. 6.
    La Rocca RV, Stein CA, Danesi R, Cooper MR, Uhrich M, Myers CE: A pilot study of suramin in the treatment of metastatic renal carcinoma. Cancer 67: 1509–1513, 1991PubMedGoogle Scholar
  7. 7.
    Motzer RJ, Nanus DM, O'Moore P, Scher HI, Bajorin DF, Reuter V, Tong WP, Iversen J, Louison C, Albino AP, Bosl GJ: Phase II trial of suramin in patients with advanced renal cell carcinoma: Treatment results, pharmacokinetics, and tumor growth factor expression. Cancer Res 52: 5775–5779, 1992PubMedGoogle Scholar
  8. 8.
    Hosang M: Suramin binds to platelet-derived growth factor and inhibits its biological activity. J Cell Biochem 29: 265–273, 1985PubMedGoogle Scholar
  9. 9.
    Coffey RJ, Leof EB, Shipley GD, Moses HL: Suramin inhibition of growth factor receptor binding and mitogenicity in AKR-28 cells. J Cell Physiol 132: 143–148, 1987PubMedGoogle Scholar
  10. 10.
    Vaisman N, Gospodarowicz D, Neufeld G: Characterization of the receptors for vascular endothelial cell growth factor. J Biol Chem 256: 19461–19466, 1990Google Scholar
  11. 11.
    Minniti CP, Maggi M, Helman LJ: Suramin inhibits the growth of human rhabdomyosarcoma by interrupting the insulin-like growth factor II autocrine growth loop. Cancer Res 52: 1830–1835, 1992PubMedGoogle Scholar
  12. 12.
    Pesenti E, Sola F, Mongelli N, Grandi M, Spreattio F: Suramin prevents neovascularization and tumor growth through blocking of basic fibroblast growth factor activity. Br J Cancer 66: 367–372, 1992PubMedGoogle Scholar
  13. 13.
    Brem S, Tsanaclis AMC, Gately S, Gross JL, Herblin WF: Immunolocalization of basic fibroblast growth factor to the microvasculature of human brain tumors. Cancer 70: 2673–2680, 1992PubMedGoogle Scholar
  14. 14.
    Zagzag D, Miller DC, Sato Y, Rifkin DB, Burstein DE: Immunohistochemical localization of basic fibroblast growth factor in astrocytomas. Cancer Res 50: 7393–7398, 1990PubMedGoogle Scholar
  15. 15.
    Stefanik DF, Rizkalla LR, Soi AS, Goldblatt A, Rizkalla WM: Acidic and basic fibroblast growth factors are present in glioblastoma multiforme. Cancer Res 51: 5760–5765, 1991PubMedGoogle Scholar
  16. 16.
    Takahashi JA, Mori H, Fukumoto M, Igarashi K, Jaye M, Oda Y, Kikuchi H, Hatanaka M: Gene expression of fibroblast growth factors in human gliomas and meningiomas: Demonstration of cellular source of basic fibroblast growth factor mRNA and peptides in tumor tissues. Proc Natl Acad Sci USA 87: 5710–5714, 1990PubMedGoogle Scholar
  17. 17.
    Okumura N, Takimoto K, Okada M, Nakagawa H: C6 glioma cells produce basic fibroblast growth factor that can stimulate their own proliferation. J Biochem 106: 904–909, 1989PubMedGoogle Scholar
  18. 18.
    Gross JL, Morrison RS, Eidsvoog K, Herblin WF, Kornblith PL: Basic fibroblast growth factor: A potential autocrine regulator of human glioma cell growth. J Neurosci Res 27: 689–696, 1990PubMedGoogle Scholar
  19. 19.
    Gross JL, Herblin WF, Eidsvoog K, Horlick R, Brem S: Tumor growth regulation by modulation of basic fibroblast growth factor. In: R Steiner, PB Weisz, R Langer (eds,), Angiogenesis: Key Principles, pp. 421–427. Switzerland: Birkhauser Verlag Basel, 1992Google Scholar
  20. 20.
    Brem S, Cotran RS, Folkman J: Tumor angiogenesis: A quantitative method for histologic grading. J Natl Cancer Inst 48: 347–356, 1972PubMedGoogle Scholar
  21. 21.
    Plate KH, Breier G, Weich HA, Risau W: Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomasin vivo. Nature 359: 845–848, 1992PubMedGoogle Scholar
  22. 22.
    Brem SS, Zagzag D, Tsanaclis AMC, Gately S, Elkouby M-P, Brien SE: Inhibition of angiogenesis and tumor growth in the brain: Suppression of endothelial cell turn over by penicillamine and the depletion of copper, an angiogenic cofactor. Am J Pathol 137: 1121–1142, 1990PubMedGoogle Scholar
  23. 23.
    Gross JL, Herblin WF, Dusak BA, Czerniak P, Diamond MD, Sun T, Eidsvoog K, Dexter DL, Yayon A: Effects of modulation of basic fibroblast growth factor on tumor growthin vivo. J Natl Cancer Inst 85: 121–131, 1993PubMedGoogle Scholar
  24. 24.
    Gagliardi A, Hadd H, Collins DC: Inhibition of angiogenesis by suramin. Cancer Res 52: 5073–5075, 1992PubMedGoogle Scholar
  25. 25.
    Shibui S, Hoshino T, Vanderlaan M, Gray JW: Double labeling with iodo- and bromodeoxyuridine for cell kinetics studies. J Histochem Cytochem 37: 1007–1011, 1989PubMedGoogle Scholar
  26. 26.
    Bullard DE, Schold C, Bigner SH, Bigner DD: Growth and chemotherapeutic response in athymic mice of tumors arising from human glioma-derived cell lines. J Neuropath Exp Neurol 40: 410–427, 1981PubMedGoogle Scholar
  27. 27.
    Bayens-Simmonds J, Boisvert DPJ, Castro ME, Johnson ES: A feline model for experimental studies of peritumor brain edema. J Neuro-Oncol 6: 371–378, 1988Google Scholar
  28. 28.
    Vignon F, Prebois C, Rochefort H: Inhibition of breast cancer growth by suramin. J Natl Cancer Inst 84: 38–42, 1992PubMedGoogle Scholar
  29. 29.
    Fantini J, Guo X-J, Marvaldi J, Rougon G: Suramin inhibits proliferation of rat glioma cells and alters N-CAM cell surface expression. Int J Cancer 45: 554–561, 1990PubMedGoogle Scholar
  30. 30.
    Scher HI, Jodrell DI, Iversen JM, Curley T, Tong W, Egorin MJ, Forrest A: Use of adaptive control with feedback to individualize suramin dosing. Cancer Res 52: 64–70, 1992PubMedGoogle Scholar
  31. 31.
    Berns EM, Schuurmans AL, Lamb DJ, Foekens JA, Mulder E: Antiproliferative effects of suramin on androgen responsive tumor cells. Eur J Cancer 26: 470–474, 1990PubMedGoogle Scholar
  32. 32.
    Jindal H, Anderson CW, Davis RG, Vishwanatha JK: Suramin affects DNA synthesis in Hela cells by inhibition of DNA polymerases. Cancer Res 50: 7754–7757, 1990PubMedGoogle Scholar
  33. 33.
    Bojanoski K, Lelievre S, Markovits J, Couprie J, Jacquemin-Sablon A, Larsen AK: Suramin is an inhibitor of DNA to-poisomerase IIin vitro and in chinese hamster fibrosarcoma cells. Proc Natl Acad Sci USA 89: 3025–3029, 1992PubMedGoogle Scholar
  34. 34.
    Jamis-Daw CA, Weiss GH, Merino MJ, Cooper MR, Linehan WM, Myers CE: Suramin selectively localizes to vascular endothelial cells: a possible basis for the antiangiogenesis activity of suramin. Proc Am Assoc Cancer Res 32: 83, 1991Google Scholar
  35. 35.
    Rago R, Tutsch K, Pomplun M, Hutson P, Wilding G: Human plasma and tissue levels of suramin. Proc Am Assoc Cancer Res 33: 429, 1992Google Scholar
  36. 36.
    Zagzag D, Brem S, Robert F: Neovascularization and tumor growth in the rabbit brain. Am J Pathol 131: 361–372, 1988PubMedGoogle Scholar
  37. 37.
    Fan T-PD, Brem S: Angiosuppression.In: The Search for New Anticancer Drugs, Cancer Biology Series. M.J. Waring and B. Ponder, (eds), Vol. 3, pp 185–229, Kluwer Publishers, Lancaster, UK, 1992Google Scholar
  38. 38.
    Jain RK: Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res 50 (Suppl 3): 814s-819s, 1990PubMedGoogle Scholar
  39. 39.
    Home M, Stein CA, La Rocca RV, Myers CE: Circulating glycosaminoglycan anticoagulant associated with suramin treatment. Blood 71: 273–279, 1988PubMedGoogle Scholar
  40. 40.
    Sola F, Mariani M, Farao M, Ballinari D, Grandi M, Erba FC: Inhibition of lung and liver tumor colonies in mice pretreated with suramin. Proc Am Assoc Cancer Res 33: 64, 1992Google Scholar
  41. 41.
    Rees S: Membranous neuronal and neuroglial inclusions produced by intracerebral injection of suramin. J Neurol Sci 36: 97–109, 1978PubMedGoogle Scholar
  42. 42.
    Anon: Therapeutic studies of primary central nervous system malignancies in adults. NIH Guide, 21 (41), RFA: CA-93-03, November 13, 1992Google Scholar
  43. 43.
    Cooper MR, Lieberman R, La Rocca RV, Gernt PR, Weinberger MS, Headlee DJ, Kohler DR, Goldspiel BR, Peck CC, Myers CE: Adaptive control with feedback strategies for suramin dosing. Clin Pharmacol Ther 52: 11–23, 1992PubMedGoogle Scholar
  44. 44.
    Baghdiguian S, Nickel P, Fantini J: Double screening of suramin derivatives on human colon cancer cells and on neural cells provides new therapeutic agents with reduced toxicity. Cancer Lett 60: 213–219, 1991PubMedGoogle Scholar
  45. 45.
    Wilks JW, Scott PS, Vrba LK, Cocuzza JM: Inhibition of angiogenesis with combination treatment of angiostatic steroids and suramin. Int J Radiat Biol 60: 73–77, 1991PubMedGoogle Scholar
  46. 46.
    Friehauf JP, Meyers CE, Sinha BK: Synergistic activity of suramin with tumor necrosis factor-α and doxorubicin on human prostate cancer cell lines. J Natl Cancer Inst 82: 1206–1209, 1990PubMedGoogle Scholar
  47. 47.
    Liu S, Ewing MW, Anglard P, Trahan E, La Rocca RV, Myers CE, Linehan WM: The effect of suramin, tumor necrosis factor and interferon-γ on human prostate carcinoma. J Urol 145: 389–392, 1991PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Shingo Takano
    • 1
  • Stephen Gately
    • 1
  • Herbert Engelhard
    • 1
  • Ana Maria C. Tsanaclis
    • 1
  • Steven Brem
    • 1
  1. 1.Division of Neurological SurgeryNorthwestern Memorial Hospital and School of MedicineChicagoUSA

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