Skip to main content
SpringerLink
Log in

Antiestrogen Therapy for Breast Cancer

Current Strategies and Future Prospects

  • Chapter
Endocrine Therapies in Breast and Prostate Cancer

Part of the book series: Cancer Treatment and Research ((CTAR,volume 39))

Abstract

In 1958, Lerner and coworkers [1] described the properties of the first non-steroidal antiestrogen, ethamoxytriphetol (MER-25) (Fig. 1). The compound is able to inhibit estrogen action in laboratory animals and acts as an antifertility agent in rats and mice [2]. The identification of anti-fertility effects provoked an intense search by the pharmaceutical industry for related compounds, which might have an application as postcoital contraceptives (‘morning-after’ pills). However, compounds like clomiphene and tamoxifen (Fig. 1), which were found to have potent antiestrogenic and antifertility [3–5] properties in the rat, were shown to induce ovulation in patients [6]. The drugs are now used in some countries, including the United States, to induce ovulation in subfertile women [7, 8]. Interest in the development of antiestrogens as clinically useful agents waned throughout the 1960s. Nevertheless, progress in an understanding of the hormone dependency of breast cancer opened up a new therapeutic application for these drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Lerner LJ, Holthaus JF, Thompson CR (1958): A non-steroidal estrogen antagonist 1-(p-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-methoxyphenylethanol. Endocrinology 63:295–318.

    Article  PubMed  CAS  Google Scholar 

  2. Segal JS, Nelson WO (1958): An orally active compound with anti-fertility effects in rats. Proc Soc Exp Biol Med 98:431–436.

    PubMed  CAS  Google Scholar 

  3. Segal JS, Nelson WO (1961): Antifertility action of chloramiphene. Anat Rec 139:273.

    Google Scholar 

  4. Harper MJK, Walpole AL (1967): A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil 13:101–119.

    Article  PubMed  CAS  Google Scholar 

  5. Harper MJK, Walpole AL (1967): Mode of action of ICI 46,474 in preventing implantation in rats. J Endocrinol 37:83–92.

    Article  PubMed  CAS  Google Scholar 

  6. Greenblatt RB, Barfield WE, Jungk EC, Roy AW (1961): Induction of ovulation with MRL-41. JAMA 178:101–104.

    PubMed  CAS  Google Scholar 

  7. Clark JH, Markaverich BM (1982): The agonist-antagonistic properties of clomiphene: a review. Pharmacol Ther 15:467–519.

    Article  Google Scholar 

  8. Furr BJA, Jordan VC (1984): The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25:127–205.

    Article  PubMed  CAS  Google Scholar 

  9. Jensen EV, Block GE, Smith S, et al (1971): Estrogen receptors and breast cancer responses to adrenalectomy: prediction of response in cancer therapy. NCI Monogr 34:55–70.

    CAS  Google Scholar 

  10. McGuire WL, Carbone PP, Volmer E (eds) (1975): Estrogen Receptors in Human Breast Cancer. New York, Raven Press.

    Google Scholar 

  11. Skidmore JR, Walpole AL, Woodburn J (1972): Effect of some triphenylethylenes on oestradiol binding in vitro to macromolecules from uterus and anterior pituitary. J Endocrinol 52:289–298.

    Article  PubMed  CAS  Google Scholar 

  12. Cole MP, Jones CTA, Todd IDH (1971): A new anti-oestrogenic agent in late breast cancer. Br J Cancer 25:270–275.

    Article  PubMed  CAS  Google Scholar 

  13. Ward HWC (1973): Antioestrogen therapy for breast cancer—a trial of tamoxifen at two dose levels. Br Med J 1:13–14.

    Article  PubMed  CAS  Google Scholar 

  14. Jordan VC, Koerner S (1975): Tamoxifen (ICI 46,474) and the carcinoma 8S oestrogen receptor. Eur J Cancer 11:205–206.

    Article  PubMed  CAS  Google Scholar 

  15. Jordan VC (1974): Antitumor activity of the antiestrogen ICI 46,474 (tamoxifen) in the dimethylbenzanthracene (DMBA)-induced rat mammary carcinoma model. J Steroid Biochem 5:354.

    Article  Google Scholar 

  16. Jordan VC (1975): The antitumour effect of tamoxifen in the dimethylbenzanthracene-induced rat mammary carcinoma model. Proceedings of the Symposium on the Hormonal Control of Breast Cancer. Alderley Park, ICI Pharmaceuticals Division PLC, Macclesfield, UK, pp 11–17.

    Google Scholar 

  17. Legha SS, Carter SK (1976): Antiestrogens in the treatment of breast cancer. Cancer Treat Rev 3:205–216.

    Article  PubMed  CAS  Google Scholar 

  18. Sutherland RL, Jordan VC (eds) (1981): Non-steroidal antioestrogens: molecular pharmacology and antitumor actions. Sydney, Australia, Academic Press.

    Google Scholar 

  19. Jordan VC (1984): Biochemical pharmacology of antiestrogen action. Pharmacol Rev 36: 245–276.

    PubMed  CAS  Google Scholar 

  20. Jordan VC (ed) (1986): Estrogen/Antiestrogen Action and Breast Cancer Therapy. Madison, University of Wisconsin Press.

    Google Scholar 

  21. Jordan VC (1976): Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12:419–424.

    Article  PubMed  CAS  Google Scholar 

  22. Nicholson RI, Golder MP (1975): The effect of synthetic antioestrogens on the growth and biochemistry of rat mammary tumors. Eur J Cancer 11:571–579.

    Article  PubMed  CAS  Google Scholar 

  23. Jordan VC, Dowse LJ (1976): Tamoxifen as an antitumor agent: effect on oestrogen binding. J Endocrinol 68:297–304.

    Article  PubMed  CAS  Google Scholar 

  24. Jordan VC, Koerner S (1976): Tamoxifen as an antitumor agent: role of oestradiol and prolactin. J Endocrinol 68:305–311.

    Article  PubMed  CAS  Google Scholar 

  25. Jordan VC, Jaspan T (1976): Tamoxifen as an antitumour agent: oestrogen binding as a predictive test for tumor response. J Endocrinol 68:453–460.

    Article  PubMed  CAS  Google Scholar 

  26. Jordan VC (1978): Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen treatment as a potential adjuvant therapy. Rev Endocr Rel Cancer (October suppl): 49–55.

    Google Scholar 

  27. Jordan VC, Dix CJ, Allen KE (1979): The effectiveness of long-term treatment in a laboratory model for adjuvant hormone therapy of breast cancer. In Salmon SE, Jones SE (eds): Adjuvant Therapy of Cancer, Vol 2. New York, Grune & Stratton pp 19–26.

    Google Scholar 

  28. Jordan VC, Allen KE, Dix CJ (1980): Pharmacology of tamoxifen in laboratory animals. Cancer Treat Rep 64:745–759.

    PubMed  CAS  Google Scholar 

  29. Jordan VC, Mirecki DM, Gottardis MM (1984): Continuous tamoxifen treatment prevents the appearance of mammary tumors in a model of adjuvant therapy. In Jones SE, Salmon SE (ed): Adjuvant Therapy of Cancer, Vol 4. New York, Grune Stratton, pp 27–33.

    Google Scholar 

  30. Osborne CK, Boldt DH, Clark GM, Trent JM (1983): Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res 43:3583–3585.

    PubMed  CAS  Google Scholar 

  31. Sutherland RL, Green MD, Hall RE, et al (1983): Tamoxifen induces accumulation of MCF-7 human mammary carcinoma cells in the G0/G1 phase of the cell cycle. Eur J Cancer Clin Oncol 19:615–621.

    Article  PubMed  CAS  Google Scholar 

  32. Jordan VC (1982): Laboratory models of hormone-dependent cancer. In Furr BJA (ed): Clinics in Oncology. Philadelphia, Saunders pp 21–40.

    Google Scholar 

  33. Jordan VC, Robinson SP (1987): Species specific pharmacology of antiestrogens: role of metabolism. Fed Proc 46:1870–1874.

    PubMed  CAS  Google Scholar 

  34. Shafie SM, Grantham FH (1980): Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 67: 51–56.

    Google Scholar 

  35. Osborne CK, Hobbs K, Clark GM (1985): Effect of estrogens and antiestrogens on growth of human breast cancer cells in athymic nude mice. Cancer Res 45:584–590.

    PubMed  CAS  Google Scholar 

  36. Gottardis MM, Robinson SP, Jordan VC (1985): Control of estrogen responsive human breast cancer cell lines in athymic mice by long-term tamoxifen therapy. Breast Cancer Res Treat 6:173.

    Google Scholar 

  37. Jordan VC, Fritz NF, Gottardis MM (1987) Strategies for breast cancer therapy with antiestrogens. J Steroid Biochem 27:493–498.

    Article  PubMed  CAS  Google Scholar 

  38. Ludwig Breast Cancer Study Group (1984): Randomized trial of chemoendocrine therapy and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastases. Lancet 1:1256–1260.

    Google Scholar 

  39. Ribeiro G, Swindell R (1985): The Christie Hospital tamoxifen (Nolvadex) adjuvant trial in operable breast carcinoma—7 year results. Eur J Cancer Clin Oncol 21:897–900.

    Article  PubMed  CAS  Google Scholar 

  40. Rose C, Mouridsen HT, Thorpe SM, et al, for the Danish Breast Cancer Cooperative Group (1985): Antiestrogen treatment of postmenopausal women with primary high-risk breast cancer 72 months of life table analysis. Rev Endor Rel Cancer 17:17–25.

    Google Scholar 

  41. Baum M, and other members of the Nolvadex Adjuvant Trial Organization (1985): Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer. Lancet 1:836–840.

    Google Scholar 

  42. Cumming FJ, Gray R, Davis TE, et al (1985): Adjuvant tamoxifen treatment of elderly women with Stage II breast cancer: a double-blind comparison with placebo. Ann Intern Med 103:324–329.

    Google Scholar 

  43. Cummings FJ, Gray R, Davis TE, et al. (1986): Tamoxifen versus placebo: double-blind adjuvant trial in elderly women with Stage II breast cancer. NCI Monogr 1:119–123.

    PubMed  Google Scholar 

  44. Tormey DC, Gray R, Taylor SG IV, et al (1986): Postoperative chemotherapy and chemo-hormonal therapy in women with node-positive breast cancer. NCI Mongr 1:75–80.

    Google Scholar 

  45. Fisher B, Redmond C, Brown A, et al (1983) Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol 1:227–241.

    PubMed  CAS  Google Scholar 

  46. Tormey DC, Jordan VC (1984): Long-term tamoxifen adjuvant therapy in node positive breast cancer: a metabolic and pilot clinical study. Breast Cancer Res Treat 4:297–302.

    Article  PubMed  CAS  Google Scholar 

  47. Tormey DC, Rasmussens P, Jordan VC (1987): Long-term adjuvant tamoxifen therapy. Breast Cancer Res Treat, Letter to the Editor (in press).

    Google Scholar 

  48. Bonadonna G, Rossi A, Tancini G, et al (1984): Adjuvant chemotherapy trials in resectable breast cancer with positive axillary nodes. The experience of the Milan Cancer Institute. In Jones SE, Salmon SE (eds): Adjuvant Therapy of Cancer, Vol 4. New York, Grune of Stratton, pp 195–206.

    Google Scholar 

  49. Jordan VC, Fritz NF, Tormey DC (1987): Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node positive patients with breast cancer. Cancer Res 47:624–630.

    PubMed  CAS  Google Scholar 

  50. Delozier T, Julien J-P, Juret P, et al (1986): Adjuvant tamoxifen in postmenopausal breast cancer: preliminary results of a randomized trial. Breast Cancer Res Treat 7:105–110.

    Article  PubMed  CAS  Google Scholar 

  51. Cuzick J, Baum M (1985): Tamoxifen and the contralateral breast. Lancet 2:282.

    Article  PubMed  CAS  Google Scholar 

  52. Gazet JC (1985): Tamoxifen prophylaxis for women at high risk for breast cancer. Lancet 2:1119.

    Article  PubMed  CAS  Google Scholar 

  53. Cuzick J, Wang DY, Bulbrook RD (1986): The prevention of breast cancer. Lancet 1:83–86.

    Article  PubMed  CAS  Google Scholar 

  54. Jordan VC (1986): Tamoxifen prophylaxis. Lancet 1:105.

    Article  PubMed  CAS  Google Scholar 

  55. Jordan VC, Fritz NF, van Beurden M (1986): Prophylactic tamoxifen. Lancet 1:910.

    Article  PubMed  CAS  Google Scholar 

  56. Basco VE, Coppin CML, Rebbeck PM (1986): Tamoxifen prophylaxis. Lancet 1:263.

    Google Scholar 

  57. Daly MJ (1986): Tamoxifen prophylaxis. Lancet 1:263.

    Google Scholar 

  58. Wong W (1986): Tamoxifen prophylaxis. Lancet 1:264.

    Google Scholar 

  59. Jordan VC (1986): Tamoxifen prophylaxis: prevention is better than cure—prevention is cure? In Cavalli F (ed): Endocrine Therapy of Breast Cancer: Concepts and Strategies. European School of Oncology Monograph, Heidelberg, Springer Verlag, pp 117–120.

    Google Scholar 

  60. Helgeson S, Wilking N, Carlson K, et al (1982): A comparative study of the estrogenic effects of tamoxifen and 17β estradiol in postmenopausal women. J Clin Endocrinol Metab 54:404–408.

    Article  Google Scholar 

  61. Ferrazzi E, Cartei G, Matarazzo R, Fiorentino M (1977): Oestrogen-like effect of tamoxifen on vaginal epithelium. Br Med J 1:1351–1352.

    Article  PubMed  CAS  Google Scholar 

  62. Sakai F, Cheix F, Clavel M, et al (1978): Increases in steroid binding globulins induced by tamoxifen in patients with carcinoma of the breast. J Endocrinol 76:219–226.

    Article  PubMed  CAS  Google Scholar 

  63. Fex G, Adielsson G, Mattson W (1981): Oestrogen-like effects of tamoxifen on the concentration of proteins in plasma. Acta Endocrinol (Copenh) 97:109–113.

    CAS  Google Scholar 

  64. Kallio S, Kangas L, Blanco G, et al (1986): A new triphenylethylene compound, Fc-1157a. I. Hormonal effects. Cancer Chemother Pharmacol 17:103–108.

    Article  PubMed  CAS  Google Scholar 

  65. Kangas L, Nieminen A-L, Blanco G, et al (1986): A new triphenylethylene compound, Fc-1157a. II. Antitumour effects. Cancer Chemother Pharmacol 17:109–113.

    Article  PubMed  CAS  Google Scholar 

  66. Ruenitz PC, Bagley JR, Mokier CM (1982): Estrogenic and antiestrogenic activity of monophenolic analogues of tamoxifen, 2-[p(1,2-diphenyl-1-butenyl)-phenoxy]-N,N dimethyl-ethylamine. J Med Chem 25:1056–1060.

    Article  PubMed  CAS  Google Scholar 

  67. Roos W, Oeze L, Löser R, Eppenburger U (1983): Antiestrogenic action of 3-hydroxy-tamoxifen in the human breast cancer cell line MCF-7. JNCI 71:55–59.

    PubMed  CAS  Google Scholar 

  68. Jordan VC, Lieberman ME, Cormier E, et al (1984): Structural requirements for the pharmacological activity of non-steroidal antiestrogens in vitro. Mol Pharmacol 26:272–278.

    PubMed  CAS  Google Scholar 

  69. Löser R, Seibel K, Roos W, Eppenburger U (1985): In vivo and in vitro antiestrogenic action of 3-hydroxytamoxifen, tamoxifen and 4-hydroxytamoxifen. Eur J Cancer Clin Oncol 21: 985–990.

    Article  PubMed  Google Scholar 

  70. Huber HJ, Stanislaus F (1985): Pharmacokinetics and metabolism of 3-hydroxytamoxifen citrate in laboratory animals. J Cancer Res Clin Oncol 109:294.

    Google Scholar 

  71. Löser R, Seibel K, Eppenburger U (1985): No loss of estrogenic or antiestrogenic activity after demethylation of diofoxifene (3-OH-tamoxifen). Int J Cancer 36:701–703.

    Article  PubMed  Google Scholar 

  72. Jordan VC, Collins MM, Rowsby L, Prestwich G (1977): A monhydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75:305–316.

    Article  PubMed  CAS  Google Scholar 

  73. Black LJ, Jones CD, Goode RL (1981): Differential interaction of antiestrogens with cytosol estrogen receptors. Mol Cell Endocrinol 22:95–103.

    Article  PubMed  CAS  Google Scholar 

  74. Coezy E, Borgna JL, Rochefort H (1982): Tamoxifen and metabolites in MCF-7 cells: correlations between binding to estrogen receptors and cell growth inhibition. Cancer Res 42:317–323.

    PubMed  CAS  Google Scholar 

  75. Scholl SM, Huff KK, Lippman ME (1983): Antiestrogenic effects of LY 117018 in MCF-7 cells. Endocrinology 113:611–617.

    Article  PubMed  CAS  Google Scholar 

  76. Jordan VC, Allen KE (1980): Evaluation of the antitumor activity of the nonsteroidal antiestrogen, monohydroxytamoxifen, in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16:239–251.

    Article  PubMed  CAS  Google Scholar 

  77. Wakeling AE, Valcaccia B (1983): Antioestrogenic and antitumor activities of a series of non-steroidal antioestrogens. J Endocrinol 99:455–464.

    Article  PubMed  CAS  Google Scholar 

  78. Jordan VC, Gosden B (1983) Inhibition of the antiuterotrophic activity o;f estrogens and antiestrogens by the short acting antiestrogen LY 117018. Endocrinology 113:463–486.

    Article  PubMed  CAS  Google Scholar 

  79. Von Angerer E, Prekajac J, Berger M (1985): The inhibitory effect of 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) on estrogen-dependent mammary tumors. Eur J Cancer Clin Oncol 21:531–537.

    Article  Google Scholar 

  80. Von Angerer E (1984): Development of new drugs for endocrine tumor chemotherapy. Cancer Treat Rev 11(suppl A):147–153.

    Article  Google Scholar 

  81. Von Angerer E, Engel J, Schneider MR, Sheldruk WS (1985):D-16726. Drugs of the Future 10:281–285.

    Google Scholar 

  82. Robinson SP, Koch R, Jordan VC (1988): In vitro estrogenic action in rat and human cells of hydroxylated derivatives of D16726 (Zindoxifene) an agent with known antimammary cancer activity in vivo. Cancer Res (in press).

    Google Scholar 

Download references

Authors
  1. V. Craig Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Douglass C. Tormey
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medicine, Division of Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

    C. Kent Osborne

Rights and permissions

Reprints and permissions

Copyright information

© 1988 Kluwer Academic Publishers, Boston

About this chapter

Cite this chapter

Jordan, V.C., Tormey, D.C. (1988). Antiestrogen Therapy for Breast Cancer. In: Osborne, C.K. (eds) Endocrine Therapies in Breast and Prostate Cancer. Cancer Treatment and Research, vol 39. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-1731-9_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4613-1731-9_7

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4612-8974-6

  • Online ISBN: 978-1-4613-1731-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation