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Estramustine in malignant glioma

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Summary

Estramustine, a carbamate ester combining 17(3-estradiol and nornitrogen mustard, has primarily been employed in the treatment of advanced prostatic carcinoma. However, a significant amount of preclinical investigation has been directed toward estramustine's activity against human malignant glioma. These studies have demonstrated that estramustine has potent antiproliferative effects against malignant glioma both in vitro and in vivo. Similar antimitotic effects also have been demonstrated for other carbamate esters. Estramustine does not impair proliferation of nonneoplastic astrocytes at concentrations that inhibit glioma cells. Although the reasons for this selective activity remain to be determined, it has been shown that malignant gliomas expresses an estramustine-specific binding site, estramustine-binding protein, more than brain tissue. In the clinical situation, an uptake and accumulation of estramustine in human glioma tissue have been demonstrated. Estramustine has been shown to enhance the cytotoxic effects of irradiation in relatively radioresistant glioma cells both in cell culture and in a rat glioma model. Estramustine has been regarded as mainly an anti-mitotic drug but recently other effects such as inhibition of DNA synthesis, induction of apoptosis, and membrane alterations have been shown. This report summarizes the preclinical observations concerning the effects of estramustine and related compounds on human malignant gliomas. These findings form the basis for proposing further laboratory and clinical investigation regarding estramustine and human malignant gliomas.

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References

  1. Sheline GE: Radiotherapy for high grade gliomas. Int J Radiation Oncology Biol Phys 18: 793–803,1990

    Google Scholar 

  2. Salford LG, Brun A, Nirfalk S: Ten-year survival among patients with supratentorial astrocytomas grade III and IV J Neurosurg 69:506–509,1988

    Google Scholar 

  3. Stenning SP, Freedman LS, Blechen NM: An overview of published results from randomized studies of nitrosoureas in primary high grade malignant glioma. Br J Cancer 56:89–90, 1987

    Google Scholar 

  4. Kornblith PL, Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68:1–17,1988

    Google Scholar 

  5. Fine HA: The basis for current treatment recommendations for malignant gliomas. J Neuro-Oncol20:111–120,1994

    Google Scholar 

  6. von Schoultz E, Lundblad D, Bergh J, Grankvist K, Henriksson R: Estramustine binding protein and anti-proliferative effect of estramustine in human glioma cell lines. Br J Cancer 58: 326–329,1988

    Google Scholar 

  7. von Schoultz E: Malignant glioma. Experimental studies with an estrogen-linked cytostatic. Doctoral dissertation, Umeá University, 1990

  8. Piepmeier JM, Keefe DL, Weinstein MA, Yoshida D, Zielinski J, Lin TT, Chen Z, Naftolin F: Estramustine and estrone analogs rapidly and reversibly inhibit deoxyribonucleic acid synthesis and alter morphology in cultured human glioblastoma cells. Neurosurg 32: 422–431,1993

    Google Scholar 

  9. Bergenheim AT. Estramustine-binding protein and cytotoxic effect of estramustine in glioma. Doctorial dissertation, Umeá University, 1994

  10. Bergenheim AT, Elfverson J, Gunnarsson PO, Hartman M, Henriksson R: Cytotoxic effect and uptake of estramustine in a rat glioma model. Int J Oncol 5: 293–299,1994

    Google Scholar 

  11. von Schoultz E, Bergenheim T, Grankvist K, Björk P, Henriksson R: Estramustine binding protein in human brain tumor tissue. J Neurosurg 74: 962–964,1991

    Google Scholar 

  12. Bergenheim AT, Bjork E Bergh J, von Schoultz E, Svedberg H, Hendriksson R: Estramustine-binding protein and specific binding of estramustine in astrocytoma. Cancer Res 54: 4974–4979,1994

    Google Scholar 

  13. Bergenheim AT, Gunnarsson PO, Edman K, von Schoultz E, Hariz MI, Henriksson R: Uptake and retention of estramustine and the presence of estramustine-binding protein in malignant brain tumors in humans. Br J Cancer 67: 358–361, 1993

    Google Scholar 

  14. Bergenheim AT, Zackrisson B, Elfverson J, Henriksson R: Synergism between estramustine and radiotherapy in a rat glioma model. (Abstract) J Neuro-Oncol (Suppl) 15: 53, 1993

    Google Scholar 

  15. Yoshida D, Piepmeier J, Weinstein M: Estramustine sensitizes human glioblastoma cells to irradiation. Cancer Res 54: 1415–1417,1994

    Google Scholar 

  16. Bergenheim AT, Zackrisson B, Elfverson J, Henriksson R: Radiosensitizing effect of estramustine in gliomas in vitro and in vivo. J Neuro-Oncol 23: 191–200,1995

    Google Scholar 

  17. Folca PJ, Glascock RF, Irvine WT: Studies with tritium-labelled hexoestrol in advanced breast cancer. Lancet 2: 796, 1961

    Google Scholar 

  18. Fex H, Hdgberg B, Könyves I: Estramustine phosphate -historical review. J Urol 23: 4–5,1984

    Google Scholar 

  19. Groupe European du Cancer du Sein: Essai clinique du phénol bis(2-chloroéthyl)carbamate d'oestradiol dans le cancer mammaire en phase avancée. Eur J Cancer 5:1–4,1969

    Google Scholar 

  20. Plym-Forshell G, Nilsson H: The distribution of radioactivity after administration of labelled estramustine phosphate (Estracyt), estradio-17β-phosphate and estradiol to rats. Acta Pharmacol Toxicol 35 (Suppl 1): 28,1974

    Google Scholar 

  21. Jonsson G: Cytotoxic agents in the treatment of prostatic carcinoma. Life Sci Monogr 1:145–159, 1969

    Google Scholar 

  22. Klein D: Behandlung mit estramustinphosphat bei fortgeschrittenen Prostatacarcinomen. Wiener Medizinische Wöchenschrift 122: 458–460,1971

    Google Scholar 

  23. Lindberg B: Treatment of rapidly progressing prostatic carcinoma with estracyt. J Urol 108: 303–306,1972

    Google Scholar 

  24. Forsgren B, Bjork P, Carlström K, Gustafsson J-A, Pousette Å, Högberg B: Purification and distribution of a major protein in rat prostate that binds estramustine, a nitrogen mustard derivate of estradiol-17β. Proc Natl Acad Sci 76: 3149–3153, 1979

    Google Scholar 

  25. Björk P, Forsgren B, Gustafsson J-Å, Pousette A, Högberg B: Partial characterization and ‘quantitation’ of a human prostatic estramustine binding protein. Cancer Res 42: 1935–1942,1982

    Google Scholar 

  26. Forsgren B, Björk P: Specific binding of estramustine to prostatic proteins. Urology 23 (suppl 6): 34–38,1984

    Google Scholar 

  27. Tew K, Hartley-Asp B: Cytotoxic properties of estramustine unrelated to alkylating and steroid constituents. J Urol 23: 28–33,1984

    Google Scholar 

  28. Tew KD, Stearns ME: Hormone-independent, non-alkylating mechanism of cytotoxicity for estramustine. Urol Res 15: 155–160,1987

    Google Scholar 

  29. Dixon R, Brooks M, Gill G: Estramustine phosphate: plasma concentrations of its metabolites following oral administration to man, rat, and dog. Res Comm Chem Pathol Pharmacol 27:17–29,1980

    Google Scholar 

  30. Andersson SB, Gunnarsson PO, Nilsson T, Plym-Forhell G: Metabolism of estramustine phosphate in patients with prostatic carcinoma. Eur J Drug Metab Pharmacoki 6:149–154,1981

    Google Scholar 

  31. Gunnarsson P-O, Plym-Forshell G, Fritjofsson A, Norlén BJ: Plasma concentrations of estramustine phosphate and its major metabolites in patients with prostatic carcinoma treated with different doses of estramustine phosphate (Estracyt®). Scand J Urol Nephrol 15: 201–206,1981

    Google Scholar 

  32. Gunnarsson PO, Andersson S-B, Johansson S-A, Nilsson T, Plym-Forshell G: Pharmacokinetics of estramustine phosphate (Estracyt®) in prostatic cancer patients.Eur J Clin Pharmacol 26: 113–119,1984

    Google Scholar 

  33. Gunnarsson PO, Davidsson T, Andersson S-B, Johansson S-A: Impairment of estramustine phosphate absorption by concurrent milk and food intake. Eur J Clin Pharmacol 38: 189–193,1990

    Google Scholar 

  34. Björk P, Fritjofsson A, Hartley-Asp B: Uptake and binding of estramustine and estromustine, metabolites of estramustine phosphate (Estracyt), in the human protate, and new aspects on the cytotoxic activity of estramustine phosphate in vitro. In: Harzmann R (ed) Experimentelle Urologie. Springer-Verlag, Berlin-Heidelberg,1985, pp 341–353

    Google Scholar 

  35. Björk P, Flücher S, Nelde H: Estramustine-binding protein- a marker for effect of therapy in prostatic carcinoma? Scand J Urol Nephrol Suppl 107: 59–64,1988

    Google Scholar 

  36. Kruse E, Hartley-Asp B: Uptake and metabolism of estramustine in the Dunning R3327H tumor. In vivo 2: 371–376, 1988

    Google Scholar 

  37. Norlen BJ, Andersson S-B, Bjork P, Gunnarsson PO, Fritjofsson A: Uptake of estramustine phosphate (Estracyt) metabolites in prostatic cancer. J Urology 140: 1058–1062, 1988

    Google Scholar 

  38. Flüchter SH, Nelde HJ, Björk P, Müntzing J, Bichler K-H: Effect of treatment on the expression of estramustine-binding protein (EMBP) in prostatic cancer patients: An immunohistochemical study. Prostate 14: 27–43,1989

    Google Scholar 

  39. Forsgren B, Gustafsson J-Å, Pousette Å, Hogberg B: Binding characteristics of a major protein in rat ventral prostate cytosol that interacts with estramustine, a nitrogen mustard derivate of 17β-estradiol. Cancer Res 39: 5155–5164.1979

    Google Scholar 

  40. Högberg B, Björk P, Carlström K, Forsgren B, Gustavsson J-A, Hökfelt T, Pousette A: The interaction of steroidal alkylating agents with binding components in the soluble fraction of the prostate. In: Prostate cancer and hormone receptors. Alan R. Liss Inc, 1979, pp 181–199

  41. Stearns M, Tew K: Antimicrotubule effects of estramustine, an antiprostatic tumor drug. Cancer Res 45: 3891–3897, 1985

    Google Scholar 

  42. Wallin M, Deinum J, Hartley-Asp B: Estramustine phosphate inhibits microtubule assembly by binding to the microtubule-associated proteins. Ann NY Acad Sci 466: 423–425, 1986

    Google Scholar 

  43. Stearns M, Tew K: Estramustine binds to MAP-2 to inhibit microtubule assembly in vitro. J Cell Sci 89: 331–342, 1988

    Google Scholar 

  44. Moraga D, Rivas-Berrios A, Farias G, Wallin M, Maccioni RB: Estramustine-phosphate binds to a tubulin binding domain on microtubule-associated proteins MAP-2 and TAU. Biochem Biophys Acta 1121: 97–103, 1992

    Google Scholar 

  45. Dahlltif B, Billström A, Cabral F, Hartley-Asp B: Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res 53: 4573–4581, 1993

    Google Scholar 

  46. von Schoultz E, Lundgren E, Hendriksson R: Effects of estramustine and its constituents on human malignant glioma cells. Anticancer Res 10: 693–696, 1990

    Google Scholar 

  47. von Schoultz E, Grankvist K, Gustavsson H, Henriksson R: Effects of estramustine on DNA and cell membrane in malignant glioma cells. Acta Onco1 30: 719–723, 1991

    Google Scholar 

  48. Engström KG, Grankvist K, Henriksson R: Early morphological detection of estramustine cytotoxicity measured as alteration in cell size and shape by a new technique of microperifusion. Eur J Cancer 27: 1288–1295, 1991

    Google Scholar 

  49. Henriksson R, Bjermer L, von Schoultz E, Grankvist K: The effect of estramustine on microtubuli is different from the direct action via oxygen radicals on DNA and cell membrane. Anticancer Res 10: 303–310, 1990

    Google Scholar 

  50. Vallbo C, Bergenheim T, Bergh A, Grankvist K, Henriksson R: DNA fragmentation induced by the antimitotic drug estramustine in malignant rat glioma but not in normal brain —suggesting an apoptotic cell death. Br J Cancer 71: 717–720, 1995

    Google Scholar 

  51. Sandström PE, Jonsson O, Grankvist K, Henriksson R: Identification of potassium flux pathways and their role in the cytotoxicity of estramustine in human malignant glioma, prostatic carcinoma, and pulmonary carcinoma cell lines. Eur J Cancer 12: 1822–1826, 1994

    Google Scholar 

  52. von Schoultz E, Gunnarsson PO, Henriksson R: Uptake, metabolism and proliferative effect of estramustine phosphate in human glioma cell lines. Anticancer Res 9: 1713–1716, 1989

    Google Scholar 

  53. Yoshida D, Cornell-Bell A, Piepmeier JM: Selective antimitotic effects of estramustine correlate with its antimicrotubule properties on glioblastoma and astrocytes. Neurosurgery 34: 863–868, 1994

    Google Scholar 

  54. Hartley-Asp B, Gunnarsson PO: Growth and cell survival following treatment with estramustine, nor-nitrogen mustard, estradiol and testosterone of a human prostatic cancer cell line (DU 145). J Urol 127: 818–822, 1982

    Google Scholar 

  55. Piepmeier JM, Pedersen PE, Greer CA: Immunohistochemical analysis of estramustine binding protein in astrocytes and glioblastoma. (Abstract). J Neuro-Onco1 19: 179, 1994

    Google Scholar 

  56. Heyns W, Peeters B, Mous J, Rombauts W, De Moor P: Purification and characterisation of prostatic binding protein and its subunits. Eur J Biochem 89: 181–186, 1978

    Google Scholar 

  57. Eklöv S, Larsson A, Bjork P, Nilsson S: The expression of estramustine-binding protein in the human prostatic cancer cell line DU 145 is not androgen dependent. Scand J Urol Nephrol 26: 119–125, 1992

    Google Scholar 

  58. Bergenheim AT, Hartman M, Bergh J, Ridderheim P-A, Henriksson R: Expression of estramustine-binding protein in ependymomas and in human and developing rat ependymal cells. J Neuro-Onco1 22: 45–53, 1994

    Google Scholar 

  59. Bergenheim AT, Karlsson AE, Stahl A, Sandström J, Hartman M, Henriksson R: Prognostic implication of estramustine-binding protein in astrocytoma. Int J Onco1 7: 349–352, 1995

    Google Scholar 

  60. Sinclair WK, Morton RA: X-ray sensitivity during the cell generation cycle of cultured Chinese hamster cells. Radiat Res 29: 450–474, 1966

    Google Scholar 

  61. Kim JH, Khil MS, Kim SH, Ryu S, Gabel M: Clinical and biological studies of estramustine as a novel radiation sensitizer. Int J Radiat Oncol Biol Phys 29: 555–557, 1994

    Google Scholar 

  62. Ruy S, Gabel M, Khil MS, Lee YJ, Kim SH, Kim JH: Estramustine: a novel radiation enhancer in human carcinoma cells. Int J Radiat Oncol Biol Phys 30: 99–104, 1994

    Google Scholar 

  63. Widmark A, Bergh A, Damber J-E, Henriksson R: Estramustin potentierar straleffekten av prostatacancer hos ratta. (Abstract) Swedish Medical Society Annual Meeting, 1991, p 268

  64. Eklov S, Essand M, Carlsson J, Nilsson S: Radiation sensitization by estramustine. Studies in cultured human prostatic cancer cells. The Prostate 21: 287–295, 1992

    Google Scholar 

  65. Widmark A, Damber J-E, Bergh A, Henriksson R: Estramustine potentiates the effects of irradiation on the Dunning (R3327) rat prostatic adenocarcinoma. Prostate 24: 79–83, 1994

    Google Scholar 

  66. Littbrand B, Révész L: The effect of oxygen on cellular survival and recovery after radiation. Br J Radiol 42: 914–924, 1969

    Google Scholar 

  67. Grankvist K, von Schoultz E, Henriksson R: New aspects on the cytotoxicity of estramustine-involvement of free-oxygen radicals. Int J Exp Clin Chemother 1: 37–42, 1988

    Google Scholar 

  68. Gupta R: Cross-resistance of nocodazole-resistant mutants of CHO cells toward other microtubule inhibitors: Similar mode of action of benzimidazole carbamate derivatives and NSC 181928 and TN-16. Molec Pharmacol 30: 142–148, 1986

    Google Scholar 

  69. McMillin JM, Seal US, Doe RP: Effect of oral estramustine phosphate on pituitary, gonodal, and adrenal function in the green monkey. Invest Urol 15: 151–154, 1977

    Google Scholar 

  70. Kiiss R, Khoury S, Richard F, Fourcade F, Frantz P, Capelle JP: Estramustine phosphate in the treatment of advanced prostatic cancer. Br J Urol 52: 29–33, 1980

    Google Scholar 

  71. Lerclercq G, Henson J-C: Biochemical assays for the selection of cytotoxic-linked estrogens with potential therapeutic activity. Cancer Treat Rep 62: 1255–1257, 1978

    Google Scholar 

  72. Korfsmeier K-H, Schulte-Fischediek R: Effects of estramustin phosphate on hypothalamus and hypophysis of the rat. Abstract. Acta Anatomica 111: 78, 1981

    Google Scholar 

  73. Müntzing J, Gunnarsson K: Preclinical pharmacology and toxicology of estramustine phosphate. Urology 23 (suppl 6): 6–10, 1984

    Google Scholar 

  74. Slack NH, Murphy GP: Clinical toxicity and long-term results of Emcyt therapy for prostatic cancer. Urology (Suppl) 23: 73–77, 1984

    Google Scholar 

  75. Blombäck M, Hedlund PO, Säwe U: Thrombosis Res 49: 11–121, 1988

    Google Scholar 

  76. Sawaya R, Zuccarello M, Elkalliny M, Nishiyama H: Postoperative venous thromboembolism and brain tumors: part I. Clinical profile. J Neuro-Onco1 14: 119–125, 1992

    Google Scholar 

  77. Kjaer TB, Nilsson T, Madson PO: Effect of estramustine phosphate on plasma testosterone during treatment of carcinoma of the prostate. Urology 5: 802–804, 1975

    Google Scholar 

  78. Sumi N, Yoshida H, Nakai K, Fujimoto S, Kameyama K, Nishiguchi Y, Tawaratani T, Yanagawa H, Nagasawa H, Enomoto H: Estramustine phosphate disodium (EMP). Oyo Yakuri 20: 757–802, 1980

    Google Scholar 

  79. Sumi N, Kameyama K, Nishiguchi Y, Fujimoto S, Tawaratani T, Nagasawa H, Enomoto H: Estramustine phosphate disodium (EMP). Oyo Yakuri 21: 549–586, 1981

    Google Scholar 

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  1. A. Tommy Bergenheim

    Present address: Department of Neurosurgery, University Hospital, S-901 85, Umeia, Sweden

Authors and Affiliations

  1. Departments of Oncology, Umeá University, S-901 85, Umeá, Sweden

    A. Tommy Bergenheim & Roger Henriksson

  2. Department of Neurosurgery, Umeá University, S-901 85, Umeá, Sweden

    A. Tommy Bergenheim

  3. Department of Neurosurgery, Yale University School of Medicine, 06510, New Haven, Connecticut, USA

    Joseph M. Piepmeier

  4. Department of Neurosurgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, 113, Tokyo, Japan

    Daizo Yoshida

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  1. A. Tommy Bergenheim
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  3. Joseph M. Piepmeier
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  4. Daizo Yoshida
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Bergenheim, A.T., Henriksson, R., Piepmeier, J.M. et al. Estramustine in malignant glioma. J Neuro-Oncol 30, 81–89 (1996). https://doi.org/10.1007/BF00177446

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