Breast Cancer Research and Treatment

, Volume 26, Issue 1, pp 15–21 | Cite as

Inhibition of growth and appearance of estrogen-dependent rat mammary tumors by 10-propargylestr-4-ene-3,17-dione, an aromatase inhibitor

  • S. J. Zimniski
  • M. E. Brandt
  • D. F. Covey
  • D. Puett
Report

Summary

The aromatase inhibitor 10-propargylestr-4-ene-3,17-dione (PED) has been evaluatedin vivo as an anticancer agent. Prolonged administration of PED to rats bearing dimethylbenzanthracene-induced mammary tumors resulted in significant regression of hormone-responsive tumors within several days. Greater than 50% regression was generally observed after 14 days of treatment, irrespective of dose (1, 5, or 50mg/kg body weight/day). In addition to tumor regression, a significantly increased incidence in tumor stasis was observed over the course of PED treatment. While all doses of PED examined were equipotent for both tumor regression and stasis, a dose-dependent inhibition of new tumor formation was observed in PED-treated rats. In control animals an average of 1.2 new tumors was observed during the experimental period; in contrast, averages of 0.5 tumors appeared in animals receiving 1mg PED/kg body weight/day, 0.1 tumors at 5 mg/kg, and at 50mg of PED/kg body weight/day, no new tumors occurred during the time PED was administered. The effects of PED on both regression of existing tumors and appearance of new tumors were reversed by co-administration of estradiol. Thus, PED impairs estrogen-dependent mammary tumor growth, resulting in cessation of new growth and regression of responsive tumors.

Key words

aromatase aromatase inhibitors breast cancer estrogen estrous cycle tumor regression 

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References

  1. 1.
    Brodie AMH, Marsh DA, Wu JT, Brodie HJ: Aromatase inhibitors and their use in controlling estrogen-dependent processes. J Steroid Biochem 11: 107–112, 1977Google Scholar
  2. 2.
    McGuire WL, Osborne CK, Clark GM, Knight WA III: Steroid hormone receptors and carcinoma of the breast. Am J Physiol 243: E99-E102, 1982Google Scholar
  3. 3.
    Henderson IC, Canellos GP: Cancer of the breast. New Engl J Med 302: 78–90, 1980Google Scholar
  4. 4.
    Jordan VC: Antiestrogens as antitumor agents. In: Hollander VP (ed) Hormonally Responsive Tumors. Academic Press, Orlando, FL, 1985, pp 219–235Google Scholar
  5. 5.
    Santen RJ: Overall experience with aminoglutethimide in the management of advanced breast cancer. In: Elsdon-Dew RW, Jackson IM, Birdwood GFB (eds) Aminoglutethimide: An Alternative Endocrine Therapy for Breast Carcinoma. The Royal Society of Medicine and Academic Press, London, 1982, pp 3–7Google Scholar
  6. 6.
    Brodie AMH, Santen RJ: Aromatase in breast cancer and the role of aminoglutethimide and other aromatase inhibitors. CRC Crit Rev Oncol Hematol 5: 361–396, 1987Google Scholar
  7. 7.
    Brodie AMH: Aromatase inhibition and its pharmacologic implications. Biochem Pharmacol 34: 3213–3219, 1985Google Scholar
  8. 8.
    Brandt ME, Puett D, Garola R, Fendl K, Covey DF, Zimniski SJ: Aromatase and aromatase inhibitors: From enzymology to selective chemotherapy. In: Hankins WD, Puett D (eds) Hormones, Cell Biology and Cancer. Perspectives and Potentials. Alan R. Liss, Inc., New York, 1988, pp 65–84Google Scholar
  9. 9.
    Covey DF: Aromatase inhibitors: specific inhibitors of estrogen biosynthesis. In: Berg D, Plempel M (eds) Sterol Biosynthesis Inhibitors: Pharmaceutical and Agrochemical Aspects. Ellis Horwood Ltd, Chichester, England, 1988, pp 534–571Google Scholar
  10. 10.
    Coombes RC, Goss P, Dowsett M, Gazet JC, Brodie A: 4-hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer. Lancet ii: 1237–1239, 1984Google Scholar
  11. 11.
    Goss PE, Powles TJ, Dowsett M, Hutchison G, Brodie AMH, Gazet JC, Coombes RC: Treatment of advanced postmenopausal breast cancer with an aromatase inhibitor, 4-hydroxyandrostenedione: Phase II report. Cancer Res 46: 4823–4826, 1986Google Scholar
  12. 12.
    Zimniski SJ, Brandt ME, Melner MH, Covey DF, Puett D: Inhibition of Leydig tumor cell steroidogenesis by 10-pro-pargylestr-4-ene-3,17-dione, an irreversible aromatase inhibitor. Cancer Res 45: 4883–4889, 1985Google Scholar
  13. 13.
    Brandt ME, Puett D, Covey DF, Zimniski SJ: Characterization of pregnant mare's serum gonadotropin-stimulated rat ovarian aromatase and its inhibition by 10-propargylestr-4-ene-3,17-dione. J Steroid Biochem 31: 317–324, 1988Google Scholar
  14. 14.
    Brandt ME, Covey DF, Zimniski SJ: The effects ofin vivo administration of 10-propargylestr-4-ene-3,17-dione on rat ovarian aromatase and estrogen levels. J Enzyme Inhib 4: 143–152, 1990Google Scholar
  15. 15.
    Covey DF, Hood WF, Parikh VD: 10-β-propynyl substituted steroids. Mechanism-based enzyme-activated irreversible inhibitors of estrogen biosynthesis. J Biol Chem 256: 1076–1079, 1981Google Scholar
  16. 16.
    McGuire WL, Julian JA: Comparison of macromolecular binding of estradiol in hormone-dependent and hormone-independent rat mammary carcinoma. Cancer Res 31: 1440–1445, 1971Google Scholar
  17. 17.
    Boylan EG, Wittliff JL: Specific estrogen binding in rat mammary tumors induced by 7,12-dimethylbenz(a)anthracene. Cancer Res 35: 506–511, 1975Google Scholar
  18. 18.
    Welsch CW: Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Brenton Huggins. Cancer Res 45: 3415–3443, 1985Google Scholar
  19. 19.
    Bradley CJ, Kledzik GA, Meites J: Prolactin and estrogen dependency of rat mammary cancers at early and late stages of development. Cancer Res 36: 319–324, 1976Google Scholar
  20. 20.
    Arafah BM, Manni A, Pearson OH: Effect of hypophysectomy and hormone replacement on hormone receptor levels and the growth of 7,12-dimethylbenz[a]anthracene-induced mammary tumors in the rat. Endocrinology 107: 1364–1369, 1980Google Scholar
  21. 21.
    DeSombre ER, Arbogast LY: Effect of the antiestrogen CI628 on the growth of rat mammary tumors. Cancer Res 34: 1971–1976, 1974Google Scholar
  22. 22.
    Jordan VC: Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 12: 419–424, 1976Google Scholar
  23. 23.
    Turcot-Lemay L, Cusan L, Seguin C, Kelly P, Labrie F: Effect of an GHRH analog on growth and hormone receptor levels in DMBA-induced mammary tumors in the rat. J Receptor Res 2: 135–151, 1981Google Scholar
  24. 24.
    Wing LY, Garrett WM, Brodie AMH: Effects of aromatase inhibitors, aminoglutethimide, and 4-hydroxyandrostenedione on cyclic rats with 7,12-dimethylbenz(a)anthraceneinduced mammary tumors. Cancer Res 45: 2425–2428, 1985Google Scholar
  25. 25.
    Brueggemeier RW, Li P-K: Effects of the aromatase inhibitor 7α-[4′-amino]phenylthio-4-androstene-3,17-dione on 7,12-dimethyl-benz[a]anthracene-induced mammary carcinoma in rats. Cancer Res 48: 6808–6810, 1988Google Scholar
  26. 26.
    Isaacs JT: Determination of the number of events required for mammary carcinogenesis in the Sprague-Dawley female rat. Cancer Res 45: 4827–4832, 1985Google Scholar
  27. 27.
    Fendl KC, Zimniski SJ: Role of tamoxifen in the induction of hormone-independent rat mammary tumors. Cancer Res 52: 235–237, 1992Google Scholar
  28. 28.
    Huggins C, Grand LC, Brillantes FP: Mammary cancer induced by a single feeding of polynuclear hydrocarbons and its suppression. Nature 189: 204–207, 1961Google Scholar
  29. 29.
    Jordan VC, Allen KE: Evaluation of the antitumor activity of the non-steroidal antiestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 16: 239–251, 1980Google Scholar
  30. 30.
    Jordan VC: Long-term tamoxifen therapy to control or to prevent breast cancer: Laboratory concept to clinical trials. In: Hankins WD, Puett D (eds) Hormones, Cell Biology and Cancer, Perspectives and Potentials. Alan R. Liss, Inc., New York, 1988, pp 105–123.Google Scholar
  31. 31.
    Brodie AMH, Marsh D, Brodie HJ: Aromatase inhibitors IV. Regression of hormone-dependent mammary tumors in the rat with 4-acetoxy-4-androstene-3,17-dione. J Steroid Biochem 10: 423–429, 1979Google Scholar
  32. 32.
    Puett D, Brandt ME, Covey DF, Zimniski SJ: Characterization of a potent inhibitor of aromatase: Inhibition of the rat ovarian enzyme and regression of estrogen-dependent mammary tumors by 10-propargylestr-4-ene-3,17-dione. In: Baulieu EE, Iacobelli S, McGuire WL (eds) Endocrinology and Malignancy. Parthenon Publ Co, Carnforth, England, 1986, pp 278–289Google Scholar
  33. 33.
    Metcalf BW, Wright CL, Burkhart JP, Johnston JO: Substrate-induced inactivation of aromatase by allenic and acetylenic steroids. J Amer Chem Soc 103: 3221–3222, 1981Google Scholar
  34. 34.
    Johnston JO, Wright CL, Metcalf BW: Biochemical and endocrine properties of a mechanism-based inhibitor of aromatase. Endocrinology 115: 776–785, 1984Google Scholar
  35. 35.
    Brodie AMH, Schwarzel WC, Shaikh AA, Brodie HF: The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen-dependent processes in reproduction and breast cancer. Endocrinology 100: 1684–1695, 1977Google Scholar
  36. 36.
    Zaccheo T, Giudici D, Lombardi P, Disalle E: A new irreversible aromatase inhibitor, 6-methylenandrosta-1,4-diene-3,17-dione (FCE24304): antitumor activity and endocrine effects in rats with DMBA-induced mammary tumors. Cancer Chemother Pharmacol 23: 47–30, 1989Google Scholar
  37. 37.
    Schieweck K, Bhatnager AS, Matter A: CGS16949A, a new nonsteroidal aromatase inhibitor: effects on hormone-dependent and independent tumorsin vivo. Cancer Res 48: 834–838, 1988Google Scholar
  38. 38.
    Zimniski SJ, Brandt ME, Covey DF, Puett D: Inhibition of aromatase activity and of endocrine-responsive tumor growth by 10-propargylestr-4-ene-3,17-dione and its 17-propionate derivative. Steroids 50: 135–146, 1987Google Scholar
  39. 39.
    Johnston JO: Biological characterization of 10-(2-propynyl) estr-4-ene-3,17-dione (MDL18,962), an enzyme-activated inhibitor of aromatase. Steroids 50: 105–120, 1987Google Scholar
  40. 40.
    Longcope C, Fernino A, Johnston JO: Inhibition of peripheral aromatization in baboons by an enzyme-activated aromatase inhibitor (MDL18,962). Endocrinology 122: 2007–2011, 1988Google Scholar

Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • S. J. Zimniski
    • 1
  • M. E. Brandt
    • 1
  • D. F. Covey
    • 2
  • D. Puett
    • 1
  1. 1.The Reproductive Sciences and Endocrinology Laboratories, Departments of Biochemistry and Molecular Biology, Medicine, and Obstetrics and GynecologyUniversity of Miami School of MedicineMiamiUSA
  2. 2.Department of PharmacologyWashington University School of MedicineSt. LouisUSA

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