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The future of new pure antiestrogens in clinical breast cancer

  • 15th San Antonio Breast Cancer Symposium — Plenary lecture
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Summary

The rationale for seeking to identify new pure antiestrogens was based on the recognition that existing antiestrogens, exemplified by tamoxifen, all possess partial agonist (estrogenic) activity. Conceptually, pure antiestrogens should be more effective than tamoxifen in ablating the mitogenic action of estrogens on breast tumor growth. The discovery and properties of the pure antiestrogens ICI 164,384 and ICI 182,780 are described and contrasted with those of tamoxifen. Key characteristics of these compounds which may be of particular relevance to their therapeutic application in the treatment of breast cancer are described. These include experimental data which predict efficacy in patients whose disease recurs during tamoxifen treatment, and the potential for pure antiestrogens to demonstrate greater efficacy than tamoxifen in first-line treatment of advanced breast cancer. The data imply that gains in efficacy could emerge as more rapid, more complete, or longer-lasting tumor remissions. Clinical trials with ICI 182,780 will reveal whether one or more of these predictions is correct.

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References

  1. Litherland S, Jackson M: Antioestrogens in the management of hormone-dependent breast cancer. Cancer Treat Revs 15:183–194, 1987

    Google Scholar 

  2. Smith I: Adjuvant tamoxifen for early breast cancer. Br J Cancer 57:527–528, 1987

    Google Scholar 

  3. EBCTCG: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339: 1–15, 1992

    Google Scholar 

  4. Powles TJ, Tillyer CR, Jones AL, Ashley SE, Treleaven J, Davey JB, McKinna JA: Prevention of breast cancer with tamoxifen — an update on the Royal Marsden Hospital Pilot Programme. Eur J Cancer Clin Oncol 26:680–684, 1990

    Google Scholar 

  5. Nayfield SG, Karp JE, Ford LG, Dorr FA, Kramer BS: Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 83:1450–1459, 1991

    Google Scholar 

  6. Harper MJK, Walpole AL: Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenyl ethylenes. Nature 212:87,1966

    Google Scholar 

  7. Harper MJK, Walpole AL: A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fert 13:101–199, 1967

    Google Scholar 

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

    Google Scholar 

  9. Jordan VC, Murphy CS: Endocrine pharmacology of antiestrogens as antitumor agents. Endoc Rev 11: 578–610, 1990

    Google Scholar 

  10. Wakeling AE: Pharmacology of antioestrogens.In Furr BJA, Wakeling AE (eds) Pharmacology and Clinical Uses of Inhibitors of Hormone Secretion and Action. Bailliere Tindall, London, 1987, pp 1–19

    Google Scholar 

  11. Green S, Chambon P: The oestrogen receptor: from perception to mechanism.In Parker MG (ed) Nuclear Hormone Receptors. Academic Press, London, 1991, pp 15–38

    Google Scholar 

  12. Bowler J, Lilley TJ, Pittam JD, Wakeling AE: Novel steroidal pure antiestrogens. Steroids 54:71–99, 1989

    Google Scholar 

  13. Wakeling AE: Therapeutic potential of pure antioestrogens in the treatment of breast cancer. J Steroid Biochem Mol Biol 37:771–775, 1990

    Google Scholar 

  14. Wakeling AE, O'Connor KM, Newboult E: Comparison of the biological effects of tamoxifen and a new antioestrogen (LY 117018) on the immature rat uterus. J Endocrinol 99:447–453, 1983

    Google Scholar 

  15. Wakeling AE: Anti-hormones and other steroid analogues.In Green B, Leake RE (eds) Steroid Hormones: A Practical Approach. IRL Press, Oxford, 1987, pp 219–236

    Google Scholar 

  16. Wakeling AE: Comparative studies on the effects of steroidal and nonsteroidal oestrogen antagonists on the proliferation of human breast cancer cells. J Steroid Biochem Mol Biol 34:183–188, 1989

    Google Scholar 

  17. Wakeling AE, Bowler J: Steroidal pure antioestrogens. J Endocrinol 112:R7–R10, 1987

    Google Scholar 

  18. Wakeling AE: Steroid antagonists as nuclear receptor blockers. Cancer Surveys 14:71–85, 1992

    Google Scholar 

  19. Fawell SE, White R, Hoare S, Sydenham M, Page M, Parker MG: Inhibition of estrogen receptor-DNA binding by the “pure” antiestrogen ICI 164,384 appears to be mediated by impaired receptor dimerization. Proc Natl Acad Sci USA 87:6883–6887, 1990

    Google Scholar 

  20. Reese JC, Katzenellenbogen BS: Examination of the DNA-binding ability of estrogen receptor in whole cells — implications for hormone-independent transactivation and the actions of antiestrogens. Mol Cell Biol 12:5431–4538, 1992

    Google Scholar 

  21. Gibson MK, Nemmers LA, Beckman WC Jr, Davis VL, Curtis SW, Korach KS: The mechanism of ICI 164,384 antiestrogenicity involves rapid loss of estrogen receptor in uterine tissue. Endocrinology 129:2000–2010, 1991

    Google Scholar 

  22. Dauvois S, Danielian PS, White R, Parker MG: Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc Natl Acad Sci USA 89:4037–4041, 1992

    Google Scholar 

  23. Wakeling AE, Bowler J: Novel antioestrogens without partial agonist activity. J Steroid Biochem 31:645–653, 1988

    Google Scholar 

  24. Wakeling AE, Dukes M, Bowler J: A potent specific pure antiestrogen with clinical potential. Cancer Res 51:3867–3873, 1991

    Google Scholar 

  25. Nicholson RI, Gotting KE, Gee J, Walker KJ: Actions of oestrogens and antioestrogens on rat mammary gland development: relevance to breast cancer prevention. J Steroid Biochem 30: 95–103, 1988

    Google Scholar 

  26. Nicholson RI, Walker KJ, Bouzubar N, Wills RJ, Gee JMW, Rushmere NK, Davies P: Estrogen deprivation in breast cancer. Ann NY Acad Sci 595:316–327, 1990

    Google Scholar 

  27. Dukes M, Miller D, Wakeling AE, Waterton JC: Antiuterotrophic effects of a pure antioestrogen, ICI 182,780: magnetic resonance imaging of the uterus in ovariectomized monkeys. J Endocrinol 135:239–247, 1992

    Google Scholar 

  28. Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattson A, Silfversward C, Skoog L, Somell A, Theve T, Wilking N, Askergren J, Hjalmar M-L: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet i:117–120, 1989

    Google Scholar 

  29. Musgrove EA, Wakeling AE, Sutherland RL: Points of action of estrogen antagonists and a calmodulin antagonist within the MCF-7 human breast cancer cell cycle. Cancer Res 49:2398–2404, 1989

    Google Scholar 

  30. Wakeling AE, Newboult E, Peters SW: Effects of antioestrogens on the proliferation of MCF-7 human breast cancer cells. Mol Cell Endocrinol 2:225–234, 1989

    Google Scholar 

  31. Stewart AJ, Johnson MD, May FEB, Westley BR: Role of insulin-like growth factors and type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J Biol Chem 265: 21172–21178, 1990

    Google Scholar 

  32. Clarke R, Brunner N, Katzenellenbogen BS, Thompson EW, Norman MJ, Koppi C, Paik S, Lippman ME, Dickson RB: Progression of human breast cancer cells from hormone-dependent to hormone-independent growth bothin vitro andin vivo. Proc Natl Acad Sci USA 86:3649–3653, 1989

    Google Scholar 

  33. Thompson EW, Katz D, Shima TB, Wakeling AE, Lippman ME, Dickson RB: ICI 164,384, a pure antagonist of estrogen-stimulated MCF-7 cell proliferation and invasiveness. Cancer Res 49:6929–6934, 1989

    Google Scholar 

  34. Bracke ME, Van Larabeke NA, Vyncke BM, Mareel MM: Retinoic acid modulates both invasion and plasma membrane ruffling of MCF-7 human mammary carcinoma cellsin vitro. Br J Cancer 63:867–872, 1991

    Google Scholar 

  35. Lykkesfeldt AE, Briand P: Indirect mechanism of oestradiol stimulation of cell proliferation of human breast cancer cell lines. Br J Cancer 53:29–35, 1986

    Google Scholar 

  36. Graham ML, Smith JA, Jewett PB, Horwitz KB: Heterogeneity of progesterone receptor content and remodeling by tamoxifen characterize subpopulations of cultured human breast cancer cells: analysis by quantitative dual parameter flow cytometry. Cancer Res 52:593–602, 1992

    Google Scholar 

  37. Lykkesfeldt AE, Sorenson EK: Effect of estrogen and antiestrogens on cell proliferation and synthesis of secreted proteins in the human breast cancer cell line MCF-7 and a tamoxifen resistant variant subline, AL-1. Acta Oncol 31:131–138, 1992

    Google Scholar 

  38. Osborne CK, Coronado EB, Robinson JP: Human breast cancer in the athymic nude mouse: cytostatic effects of long-term antiestrogen therapy. Eur J Cancer Clin Oncol 23:1189–1196, 1987

    Google Scholar 

  39. Gottardis MM, Jordan VC: Development of tamoxifenstimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48:5183–5187, 1988

    Google Scholar 

  40. Gottardis MM, Jiang S-Y, Jeng M-H, Jordan VC: Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49:4090–4093, 1989

    Google Scholar 

  41. Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M: Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxy-tamoxifen. J Natl Cancer Inst 83:1477–1482, 1991

    Google Scholar 

  42. Osborne CK, Wiebe VJ, McGuire WL, Ciocca DR, DeGregorio MW: Tamoxifen and the isomers of 4-hydroxytamoxifen in tamoxifen-resistant tumors from breast cancer patients. J Clin Oncol 10:304–310, 1992

    Google Scholar 

  43. Wiebe VJ, Osborne CK, McGuire WL, DeGregorio MW: Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors. J Clin Oncol 10:990–994, 1992

    Google Scholar 

  44. Howell A, Dodwell DJ, Anderson H, Redford J: Response rate after withdrawal of tamoxifen and progestogens in advanced breast cancer. Ann Oncol 3: 611–617, 1992

    Google Scholar 

  45. Lien EA, Solheim E, Ueland PM: Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res 51:4837–4844, 1991

    Google Scholar 

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  1. Bioscience I, ICI Pharmaceuticals, Alderley Park, SK10 4TG, Macclesfield, Cheshire, United Kingdom

    Alan E. Wakeling

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Wakeling, A.E. The future of new pure antiestrogens in clinical breast cancer. Breast Cancer Res Tr 25, 1–9 (1993). https://doi.org/10.1007/BF00662395

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