The future of antihormone therapy: innovations based on an established principle

  • Karsten Parczyk
  • Martin R. Schneider
Review

Abstract

Endocrine therapy of mammary and prostate cancer has been established for decades. The therapies available to block sex-hormone-receptor-mediated tumor growth are based on two principles: (i) ligand depletion, which can be achieved surgically, by use of luteinizinghormone-releasing hormone analogues or inhibitors of enzymes involved in steroid biosynthesis or by interfering with the feedback mechanisms of sex hormone synthesis at the pituitary/hypothalamic level; (ii) blockade of sex hormone receptor function by use of antihormones. The antiestrogen tamoxifen, which is the compound of choice for the treatment of mammary carcinoma, has the drawback of being a partial agonist. A complete blockade of estrogen receptor (ER) function can be achieved by a new class of compounds, pure antiestrogens. In contrast to aromatase inhibitors, pure antiestrogens are able to block ER activation by ligands other than estradiol and can also interfere with ligand-independent ER activation. In addition to estradiol, progesterone has a strong proliferative effect in mammary carcinomas. Antiprogestins are promising new tools for clinical breast cancer therapy. These compounds clearly need a functionally expressed progesterone receptor to block tumor growth, but there is strong experimental evidence that their tumor inhibition is based on more than just progesterone antagonism. The ability of these compounds to induce tumor cell differentiation that leads to apoptosis is unique among all other endocrine therapeutics. In prostate tumors that have relapsed from current androgen-ablation therapies the androgen receptor (AR) is still expressed and, compared to the primary tumors, its level is often even enhanced. Mutated AR that can be activated by other compounds such as adrenal steroids, estrogens, progestins and even antiandrogens have been detected in recurrent tumors. Thus, relapse of tumors under the selective pressure of common androgen-ablation therapies can be caused by acquired androgen hypersensitivity and AR activation by ligands other than (dihydro-)testosterone. There is a clinical need for future compounds that produce a complete blockade of AR activity even in recurrent tumors. Preclinical experiments indicate that combination therapy as well as the extension of endocrine treatments to several other tumor entities are promising approaches for further developments. Examples are the combination of antiestrogens and antiprogestins for breast cancer treatment, or the treatment of prostate carcinomas with antiprogestins.

Key words

Antihormones Total receptor blockade Ligand-independent activation Receptor gene amplification and mutation Differentiation Apoptosis 

Abbreviations

LH

luteinizing hormone

LHRH

luteinizing-hormone-releasing hormone

PR

progesterone receptor

ER

estrogen receptor

AR

androgen receptor

CPA

cyproterone acetate

EGF

epidermal growth factor

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References

  1. Angerer E von, Biberger C, Leichtl S (1995) Studies on heterocycle based pure antagonists. Ann NY Acad Sci 761:176–191Google Scholar
  2. Boring CC, Squires TS, Tong T (1993) Cancer statistics. CA 43:7–26Google Scholar
  3. Brinkmann AO, Trapman J (1995) Mutant androgen receptors in endocrine-related cancer. Endocr Relat Cancer 2:203–214Google Scholar
  4. Brooks JR, Berman C, Nguyen H, Prahalada S, Primka RL, Rasmusson GH, Slater EE (1991) Effect of castration, DES, flutamide, and the 5α-reductase inhibitor, MK-906, on the growth of the Dunning rat prostatic carcinoma, R-3327. Prostate 18:215–227Google Scholar
  5. Colombel M, Symmans F, Gil S, O'Toole KM, Chopin D, Benson M, Olsson CA, Korsmeyer S, Buttyan R (1993) Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone-refractory human prostate cancers. Am J Pathol 143:390–400Google Scholar
  6. Crawford E, Eisenberger MA, McLeod, DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ (1989) A controlled trial of leuprolide with and without flutamide in prostatic carcinoma N Engl J Med 321:419–424Google Scholar
  7. Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, Bartsch G, Klocker H (1994) Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 54:5474–5478Google Scholar
  8. Dæhlin L, Bergh A, Damber JE (1987) Direct effects of oestradiol on growth and morphology of the Dunning R3327H prostatic carcinoma. Urol Res 15:169–172Google Scholar
  9. Dauvois S, Danielian PS, White R, Parker MG (1992) Antiestrogen ICI 164, 384 reduces cellular estrogen receptor content by increasing its turnover Proc Natl Acad Sci USA 89:4037–4041Google Scholar
  10. Dauvois S, White R, Parker MG (1993) The antiestrogen ICI 182780 discrupts estrogen receptor nucleocytoplasmic shuttling. J Cell Sci 106:1377–1388Google Scholar
  11. DeFriend DJ, Howell A (1994) Tamoxifen withdrawal responseschance observations or clinical clues to antioestrogen, resistance? Breast 3:199–201Google Scholar
  12. Delabre K, Guiochon-Mantel, A, Milgrom E (1993) In vivo evidence against the existence of antiprogestins disrupting receptor binding to DNA. Proc Natl Acad Sci USA 90:4421–4425Google Scholar
  13. Dukes M, Chester R, Yarwood L, Wakeling AE (1994) Effects of a non-steroidal pure antioestrogen, ZM 189,154, on oestrogen target organs of the rat including bones. J Endocrinol 141:335–341Google Scholar
  14. Dupont A, Gomez JL, Cusan L, Koutsilieris M, Labrie F (1993) Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol 150:908Google Scholar
  15. Eaton CL, Griffiths K (1990) The role of endocrine therapy in prostatic cancer. In: Shalet SM (ed). Clinical endocrinology and metabolism vol 4. Baillière Tindall, London, pp 85–96Google Scholar
  16. El Etreby MF, Habenicht UF, Louton T, Nishino Y, Schröder G (1987) Effect of cyproterone acetate in comparison to flutamide and megestrol acetate on the ventral prostate, seminal vesicle, and adrenal glands of adult male rats. Prostate 11:361–375Google Scholar
  17. Forbes A, Wilkinson ML, Iqbal MJ, Johnson PJ, Williams R (1987) Response to cyproterone acetate treatment in primary hepatocellular carcinoma is related to fall in free 5α-dihydrotestosterone. Eur J Cancer Clin Oncol 23:1659–1664Google Scholar
  18. Geller J (1993) Basis for hormonal management of advanced prostate cancer. Cancer 71:1039–1045Google Scholar
  19. Gottardis MM, Jiang SY, Jeng MH, Jordan VC (1989) Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic by novel steroidal antiestrogens. Cancer Res 49:4090–4093Google Scholar
  20. Gronemeyer H, Benhamou B, Berry MT, Gofflo D, Garcia T, Lerone T, Metzger D, Meyer ME, Tora L, Vergezac A, Chambon D (1992) Mechanism of antihormone action. J Steroid Biochem Mol Biol 41:217–221Google Scholar
  21. Haak HR, Keizer RJW de, Hagennouw-Taal JCW, Seters AP van, Vielvoye GJ, Dulken H van (1990) Successful mifepristone treatment of recurrent, inoperable meningioma. Lancet 336:124–125Google Scholar
  22. Horn DW, Vollmer G, Deerberg F, Schneider MR (1993) The EnDA endometrial adenocarcinoma: an oestrogen-sensitive, metastasizing, in vivo tumor model of the rat. J Cancer Res Clin Oncol 119:450–456Google Scholar
  23. Horn DW, Vollmer G, Angerer E von, Schneider MR (1994) Effect of the nonsteroidal antiestrogen ZK 119.010 on growth and metastasis of the EnDA endometrial carcinoma. Int J Cancer 58:426–429Google Scholar
  24. Horvath G, Stendahl U, Kalling M, Fernüo M, Himmelmann A, Hajba A (1990) Antiestrogenic treatment of advanced and recurrent carcinoma corpus uteri—a phase-II study of toremifene. Anticancer Res 10:323–326Google Scholar
  25. Horwitz KB (1992) The molecular biology of RU 486. Is there a role for antiprogestins in the treatment of breast cancer? Endocr Rev 13:1–17Google Scholar
  26. Howell A, Dodwell DJ, Anderson H (1990) New endocrine approaches to breast cancer. In: Shalet SM (ed). Clinical endocrinology and metabolism, vol 4. Baillière Tindall, London, pp 67–84Google Scholar
  27. Howell A, DeFriend D, Robertson J, Blamey R, Walton P (1995) Response to a specific antioestrogen (ICI 182780) in tamoxifenresistant breast cancer. Lancet 345:29–30Google Scholar
  28. Huisman TWA, Tanghe HLJ, Koper JW, Reubi JC, Foekens JA, Avezaat CJJ, Braakman R, Lamberts SWJ (1991) Progesterone, oestradiol, somatostatin and epidermal growth factor receptors on human meningiomas and their CT characteristics. Eur J Cancer 27:1453–1457Google Scholar
  29. Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA, Korach KS (1992) Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc. Natl Acad Sci USA 89:4658–4662Google Scholar
  30. Iveson TJ, Smith IE, Ahern J, Smithers DA, Trunet PF, Dowsett M (1993) Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res 63:266–270Google Scholar
  31. Jordan VC (1993) A current view of tamoxifen for the treatment and prevention of breast cancer. Br J Pharmacol 110:507–517Google Scholar
  32. Kiang DT, Kollander RE, Thomas T, Kennedy BJ (1989) Up-regulation of estrogen receptors by nonsteroidal antiestrogens in human breast cancer. Cancer Res 49:5312–5316Google Scholar
  33. Labrie F, Belanger A, Dupont A, Luu-The V, Simard J, Labrie C (1993) Science behind total androgen blockade: from gene to combination therapy. Clin Invest Med 16:475–492Google Scholar
  34. Li M, Spitzer E, Zschiesche W, Binas B, Parczyk K, Grosse R (1995) Antiprogestins inhibit growth and stimulate differentiation in the normal mammary gland. J Cell Physiol 164:1–8Google Scholar
  35. Maasberg M, Rotsch M, Jaques G, Enderle-Schmidt U, Weehle R, Havemann K (1989) Androgen receptors, androgen-dependent proliferation, and 5α-reductase activity of small-cell lung cancer cell lines. Int J Cancer 43:685–691Google Scholar
  36. Madjno R, Parczyk K, Michna H, Schneider MR (1995) The impact of tamoxifen and the pure antiestrogen ZM 182780 on the estrogen and progesterone receptor levels in rat mammary carcinoma and uterine tissue. In: 12th International Symposium of the Jouranl of Biochemistry and Molecular Biology, 21–24 May 1995, BerlinGoogle Scholar
  37. McDonnell DP, Goldman ME (1994) RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism. J Biol Chem 269:11945–11949Google Scholar
  38. McDonnell DP, Vegeto E, O'Malley BW (1992) Identification of a negative regulatory function for steroid receptors. Proc Natl Acad Sci USA 89:10563–10567Google Scholar
  39. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LWK, Hsieh JT, Tu SM, Campbell ML (1992) Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 52:6940–6944Google Scholar
  40. Michna H, Schneider MR, Nishino Y, El Etreby MF (1989) The antitumor mechanism of progesterone antagonists is a receptor mediated antiproliferative effect by induction of terminal cell death. J Steroid Biochem 34:447–453Google Scholar
  41. Michna H, Fritzemeier KH, Parczyk K, Nishino Y, Schneider MR (1996) Antiprogestin-progesterone interactions. In: Lippmann ME, Dickson RB (eds) Breast cancer: cellular and molecular biologyGoogle Scholar
  42. Mobbs BG, Johnson IE, Liu Y (1990) Quantitation of cytosolic and nuclear estrogen and progesterone receptor in benign, untreated, and treated malignant human prostatic tissue by radioligand binding and enzyme-immunoassays. Prostate 16:235–244Google Scholar
  43. Muss HB (1992) Endocrine therapy for advanced breast cancer: a review. Breast Cancer Res Treat 21:15–26Google Scholar
  44. Neumann F (1983) Pharmacological basis for clinical use of antiandrogens. J Steroid Biochem 19:391–402Google Scholar
  45. Nicholson RI, Francis AB, McClelland RA, Manning DL, Gee JMW (1994) Pure anti-oestrogens (ICI 164384 and ICI 182780) and breast cancer: is the attainment of complete oestrogen withdrawal worthwile? Endocr Relat Cancer 1:5–17Google Scholar
  46. Nieh PT (1995) Withdrawal phenomenon with the antiandrogen casodex. J Urol 153:1070–1073Google Scholar
  47. Nishino Y, Schneider MR, Michna H (1994) Enhancement of the antitumor efficacy of the antiprogestin, onapristone, by combination with the antiestrogen, ICI 164384. J Cancer Res Clin Oncol 120:298–302Google Scholar
  48. Osborne CK, Ester B, Coronado-Heinsohn, Susan G, Hilsenbeck, Bryant L, McCue, Wakeling AE, Richard A, McClelland, Manning DL, Nicholson RI (1995) Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 87:746–750Google Scholar
  49. Parczyk K, Madjno R, Angerer E von, Schneider MR (1995) Various pure antiestrogens downregulated the ER while partial agonists do not. In: 12th International Symposium of the Journal of Steroid Biochemistry and Molecular Biology, 21–24 May 1995, BerlinGoogle Scholar
  50. Parczyk K, Michna H (1996) Androgen withdrawal reduces androgen receptor immunoreactivity in rat prostate carcinoma in contrast to androgen receptor antagonists. J Steroid Biochem Mol BiolGoogle Scholar
  51. Park R, Grigsby PW, Muss H, Norris HJ (1992) Corpus: epithelial tumors. In: Hoskins W, Perez C, Young R (eds) Principles and practice of gynaecologic oncology. Lippincott, Philadelphia, pp 663–693Google Scholar
  52. Patterson JS (1981) Clinical aspects and development of anti-oestrogen therapy: a review of the endocrine effects of tamoxifen in animals and man. J Endocrinol 89:67P-75PGoogle Scholar
  53. Petrow V (1986) The dihydrotestosterone (DHT) hypothesis of prostate cancer and its therapeutic implications. Prostate 9:343–361Google Scholar
  54. Pham TA, Elliston JF, Nawaz Z, McDonnell DP, Tsai MJ, O'Malley BW (1991) Antiestrogen can establish nonproductive receptor complexes and alter chromatin structure at target enhances. Proc Natl Acad Sci USA 88:3125–3129Google Scholar
  55. Raghaven D (1988) Non-hormone chemotherapy for prostate cancer: principles of treatment and application to the testing of new drugs. Semin Oncol 15:371–389Google Scholar
  56. Reed JC (1994) Bcl-2 and the regulation of programmed cell death. J Cell Biol 124:1–6Google Scholar
  57. Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleum-Mooijman MC, Trapman J, Brinkmann AO, Santerse AB, Schroder FH, van derKwast TH (1994) Androgen receptor status in localized and locally progressive hormone refractory human. Am J Pathol 144:735–46Google Scholar
  58. Santen RJ, Manni A, Harvey H, Redmond C (1990) Endocrine treatment of breast cancer in women. Endocr Rev 11:221–265Google Scholar
  59. Savouret JF, Bailly A, Misrahi M, Rauch C, Redeuilh G, Chauchereau A, Milgrom E (1991) Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene. EMBO J 10:1875–1883Google Scholar
  60. Scher HI, Kelly WK (1993) The flutamide withdrawal syndrome: Its impact on clinical trials in hormone-refractory prostatic cancer. J Clin Oncol 11:1566–1572Google Scholar
  61. Schieweck K, Bhatnagar AS, Batzl CH, Lang M (1993) Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors. J Steroid Biochem Mol Biol 44:633–636Google Scholar
  62. Schneider MR (1993) Antihormone: Von der Entdeckung der Steroidhormone zu spezifischen Krebstherapeutika. Arch Pharm (Weinheim) 326:769–784Google Scholar
  63. Schneider MR, Michna H, Nishino Y, El Etreby MF (1989) Antitumor activity of the progesterone antagonists ZK 98299 and RU486 in the hormone-dependent MXT mammary tumor model of the mouse and the DMBA- and MNU-induced mammary tumor model of the rat. Eur J Cancer Clin Oncol 25:691–701Google Scholar
  64. Schneider MR, Humm A, Graf AH (1990a) The tumor-inhibiting effect of diethylstilbestrol and its diphosphate on the Nb−H and Nb−R prostatic carcinomas of the rat. J Cancer Res Clin Oncol 116:159–167Google Scholar
  65. Schneider MR, Michna H, Nishino Y, El Etreby MF (1990b) Antitumor activity and mechanism of action of different antiprogestins in experimental breast cancer models. J Steroid Biochem Mol Biol 37:783–787Google Scholar
  66. Schneider MR, Michna H, Nishino Y, Henderson D (1991) Antitumor activity and mechanism of action of progesterone antagonists in experimental breast cancer. In: Masobrio M, Menato G, Cassoni P, Simonetta M (eds) Attualita endocrine in oncologia ginecologica e in medicina del riproduzione. Monduzzi, Bologna, pp 99–105Google Scholar
  67. Schneider MR, Michna H, Habenicht UF, Nishino Y, Grill HJ, Pollow K (1992) The tumor-inhibiting potential of the progesterone antagonist onapristone in the human mammary carcinoma T61 in nude mice. J Cancer Res Clin Oncol 118:187–189Google Scholar
  68. Smith CL, Conneely OM, O'Malley BW (1993) Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone. Proc Natl Acad Sci USA 90:6120–6124Google Scholar
  69. Steinberg GD, Isaacs JT (1993) Pharmacological approaches to the management of metastatic prostatic cancer. In: Hickman JA, Tritton TR (eds) Cancer chemotherapy. Blackwell, London, pp 322–343Google Scholar
  70. Steiner JF (1993) Finasteride: a 5α-reductase inhibitor. Clin Pharm 12:15–23Google Scholar
  71. Taplin ML, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN, Balk SP (1995) Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 332:1393–1398Google Scholar
  72. Truss M, Bartsch J, Beato M (1994) Antiprogestins prevent progesterone receptor binding to hormone responsive elements in vivo Proc Natl Acad Sci USA 91:11333–11337Google Scholar
  73. Tucker H (1990) Non-steroidal anti-androgens in the treatment of prostate cancer. Drug Future 15:255–265Google Scholar
  74. Van de Velde P, Nique F, Bouchoux F, Brémaud J, Hameau M-C, Lucas D, Moratille C, Viet S, Philibert D, Teutsch G (1994) RU 58 668, a new pure antiestrogen inducing a regression of human mammary carcinoma implanted in nude mice. J Steroid Biochem Mol Biol 48:187–196Google Scholar
  75. Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9:401–406Google Scholar
  76. Vollmer G, Schneider MR (1996) The rat endometrial adenocarcinoma cell line Ruca-I: a novel hormone-responsive in vivo/in vitro tumor model. J Steroid Biochem Mol BiolGoogle Scholar
  77. Voogt HJ de (1992) The position of cyproterone acetate (CPA), a steroidal anti-androgen, in the treatment of prostate cancer. Prostate 4:91–95Google Scholar
  78. Wakeling AE (1985) Chemical structure and pharmacology of antioestrogens. History, current trends and future prospects. In: Pannuti F (ed) Anti-oestrogens in oncology. Past, present and prospects. Excerpta Medica, Amsterdam Geneva. Hong Kong, pp 43–53Google Scholar
  79. Wakeling AE (1989) Comparative studies on the effects of steroidal and nonsteroidal oestrogen antagonists on the proliferation of human breast cancer cells. J Steroid Biochem 34:183–188Google Scholar
  80. Wakeling AE, Bowler J (1987) Steroidal pure antiestrogens. J Endocrinol 112:R7-R10Google Scholar
  81. Wakeling AG, Dukes M, Bowler J (1991) A potent specific pure antiestrogen with clinical potential. Cancer Res 51:3867–3873Google Scholar
  82. Weinbauer GF, Nieschlag E (1992) LH-RH antagonists: state of the art and future perspectives. Recent Results Cancer Res 124:113–136Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Karsten Parczyk
    • 1
  • Martin R. Schneider
    • 1
  1. 1.Experimental OncologyResearch Laboratories of Schering AGBerlinGermany

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