Direct Antitumor Effects of LH-RH Analogs

  • J. A. Foekens
  • J. G. M. Klijn
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 124)


Luteinizing hormone releasing hormone (LH-RH) is a hypothalamic decapeptide secreted in a pulsatile way which leads to an increase in pituitary LH-RH receptor numbers and gonadotropin secretion [1]. Exposure of the pituitary gland to supraphysiological concentrations of LH-RH or continuously to long-acting LH-RH agonists causes downregulation of LH-RH receptors and loss of responsiveness (see review [2]). The presence of LH-RH or LH-RH-like peptides has not only been detected in the hypothalamus, but also in human biological fluids, the central nervous system, and a variety of normal and tumor tissues (see review [3]). This, together with the presence of LH-RH receptors in a wide range of normal and tumor tissues [3], has resulted in the suggestion that LH-RH may have a paracrine or autocrine role in the local regulation of cell biological processes. In the present report we summarize the literature with special emphasis on direct antitumor actions of LH-RH analogs on classical hormone-regulated cancers, i.e., of the breast, the prostate, and the ovaries.


Human Breast Cancer Cell Luteinizing Hormone Release Hormone LHRH Agonist Luteinizing Hormone Release Hormone Analog Luteinizing Hormone Release Hormone Agonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Clayton RN (1982) Gonadotropin-releasing hormone modulation of its own pituitary receptors: evidence for biphasic regulation. Endocrinology 111:152PubMedCrossRefGoogle Scholar
  2. 2.
    Furr BJA, Woodburn JR (1988) Luteinizing hormone-releasing hormone an its analogues: a review of biological properties and clinical uses. J Endocrinol Invest 11:535PubMedGoogle Scholar
  3. 3.
    Klijn JGM, Foekens JA (1989) Extrapituitary actions. In: Vickery BH, Lunenfeld B (eds) GnRH analogues in cancer and human reproduction, vol 1, Basic aspects. Kluwer, Dordrecht, p 71Google Scholar
  4. 4.
    Klijn JGM, de Jong FH (1982) Treatment with a lutemizing-hormone-releasing-hor-mone analogue (buserelin) in premenopausal patients with metastatic breast cancer. Lancet i: 1213CrossRefGoogle Scholar
  5. 5.
    Manni A, Santen R, Harvey H, Lipton A, Max D (1986) Treatment of breast cancer with gonadotropin-releasing hormone. Endocr Rev 7:89PubMedCrossRefGoogle Scholar
  6. 6.
    Klijn JGM, Foekens JA (1988) Long-term peptide hormone treatment with LH-RH agonists in metastatic breast cancer. In: Santen RJ, Juhos E (eds) Endocrine-dependent breast cancer: critical assessment of recent advances. Huber, Toronto, p 92Google Scholar
  7. 7.
    Schally AV, Arimura A, Coy AH (1980) Recent approaches to fertility control based on derivatives of LH-RH. Vitam Horm 38:257PubMedCrossRefGoogle Scholar
  8. 8.
    Harvey HA, Lipton A, Max DT (1984) LH-RH analogs for human mammary carcinoma. In: Vickery BH, Nestor JJ, Hafez ESE (eds) LH-RH and its analogs, contracep-tive and clinical application. MTP, Lancaster, p 329Google Scholar
  9. 9.
    Schwartz L, Guiochet N, Keiling R (1988) Two partial remissions induced by an LHRH analogue in two postmenopausal women with metastatic breast cancer. Cancer 62:2498PubMedCrossRefGoogle Scholar
  10. 10.
    Plowman PN, Nicholson RI, Walker KJ (1986) Remissions of metastatic breast cancer in postmenopausal women with luteinizing hormone releasing hormone (ICI 118630) therapy. Eur J Cancer Clin Oncol 22:746CrossRefGoogle Scholar
  11. 11.
    Waxman JH, Harlend SJ, Coombes RC, Wrigley PFM, Malpas JS, Powles T, Lister TA (1985) The treatment of postmenopausal women with advanced breast cancer with buserelin. Cancer Chemother Pharmacol 15:171PubMedCrossRefGoogle Scholar
  12. 12.
    Harris AL, Carmichael J, Cantwell, Dowsett M (1989) Zoladex: endocrine and therapeutic effects in post-menopausal breast cancer. Br J Cancer 59:97PubMedCrossRefGoogle Scholar
  13. 13.
    Crighton IL, Dowsett M, Lai A, Man A, Smith IE (1989) Use of luteinising hormone-releasing hormone agonist (leuprolin) in advanced post-menopausal breast cancer: clinical and endocrine effects. Br J Cancer 60:644PubMedCrossRefGoogle Scholar
  14. 14.
    Sarda AK, Nair RMG (1981) Elevated levels of LRH in human milk. J Clin Endocrinol Metab 52:647CrossRefGoogle Scholar
  15. 15.
    Amarant T, Fridkin M, Koch Y (1982) Luteinizing hormone-releasing hormone and thyrotropin releasing hormone in human and bovine milk. Eur J Biochem 127:647PubMedCrossRefGoogle Scholar
  16. 16.
    Seppälä M, Wahlström T (1980) Identification of luteinizing hormone-releasing factor and alpha subunit of glycoprotein hormones in ductal carcinoma of the mammary gland. Int J Cancer 26:267PubMedCrossRefGoogle Scholar
  17. 17.
    Bützow R, Huhtaniemi I, Clayton R, Wahlström T, Andersson LC, Seppälä M (1987) Cultured mammary carcinoma cells contain gonadotropin-releasing hormone-like im-munoreactivity, GnRH binding sites and chorionic gonadotropin. Int J Cancer 39:498PubMedCrossRefGoogle Scholar
  18. 18.
    Eidne KA, Harris NS, Millar RP, Wilcox J (1987) GnRH-immunoreactivity and GnRH m-RNA in two human breast cancer cell lines MDA-MB-231 and ZR-75-1. 69th Annual Meeting of the Endocrine Society, Indianapolis, 10-12 June, 653Google Scholar
  19. 19.
    Ciocca DR, Puy La, Fasoli LC, Tello O, Aznar JC, Gago FE, Papa SI, Soneho R (1990) Corticotropin-releasing hormone, luteinizing hormone-releasing hormone, and somato-statin-like immunoreactivities in biopsies from breast cancer patients. Breast Cancer Res Treat 15:175PubMedCrossRefGoogle Scholar
  20. 20.
    Miller WR, Scott WN, Morris R, Fraser HM, Sharpe RM (1985) Growth of human breast cancer cells inhibited by a luteinizing hormone-releasing hormone agonist. Nature 313:231PubMedCrossRefGoogle Scholar
  21. 21.
    Eidne KA, Flanagan CA, Millar RP (1985) Gonadotropin-releasing hormone binding sites in human breast carcinoma. Science 229:989PubMedCrossRefGoogle Scholar
  22. 22.
    Miller WR, Scott WN, Fraser HM, Sharpe RM (1987) Direct inhibition of human breast cancer cell growth by an LHRH agonist. In: Klijn JGM, Paridaens R, Foekens JA (eds) Hormonal manipulation of cancer: peptides, growth factors, and new (anti) steroidal agents. Raven, New York, p 357 (EORTC monograph series, vol 18)Google Scholar
  23. 23.
    Eidne KA, Flanagan CA, Harris NS, Millar RP (1987) Gonadotropin-releasing hormone (GnRH)-binding sites in human breast cancer cell lines and inhibitory effects of GnRH antagonists. J Clin Endocrinol Metab 64:425PubMedCrossRefGoogle Scholar
  24. 24.
    Fekete M, Wittliff JL, Schally AV (1989) Characterization and distribution of receptors for [D-Trp6]-luteinizing-hormone-releasing hormone, somatostatin, epidermal growth factor, and sex steroids in 500 biopsy samples of human breast cancer. J Clin Lab Analysis 3:137CrossRefGoogle Scholar
  25. 25.
    Fekete M, Bajusz S, Groot K, Csernus VJ, Schally AV (1989) Comparison of different agonists and antagonists of luteinizing hormone-releasing hormone for receptor-binding ability to rat pituitary and human breast cancer membranes. Endocrinoloty 124:946CrossRefGoogle Scholar
  26. 26.
    Vincze B, Pályi I, Daubner D, Kremmer T, Számel I, Bodrogi I, Sugar J, Seprôdi J, Mezô I, Teplán I, Eckhardt S (1991) Influence of luteinizing hormone-releasing hormone agonists on human mammary carcinoma cell Unes and their xenografts. J Steroid Biochem Mol Biol 38:119PubMedCrossRefGoogle Scholar
  27. 27.
    Corbin A (1982) From contraception to cancer: a review of the therapeutic applications of LH-RH analogues as antitumor agents. Yale J Biol Med 55:27PubMedGoogle Scholar
  28. 28.
    Matsuzawa A, Yamamoto T (1982) Enhanced and reversed growth in vitro of a pregnancy-dependent mouse mammary tumor (TPDMT-4) by a gonadotropin-releasing hormone agonist analog. Eur J Cancer Clin Oncol 18:495PubMedCrossRefGoogle Scholar
  29. 29.
    Blankenstein MA, Henkelman MS, Klijn JGM (1983) An analogue of LHRH antagonizes the growth-stimulatory effect of estradiol on human breast cancer cells in culture (MCF-7). J Steroid Biochem 19 (Suppl):95 SCrossRefGoogle Scholar
  30. 30.
    Blankenstein MA, Henkelman MS, Klijn JGM (1985) Direct inhibitory effect of a luteinizing hormone-releasing hormone agonist on MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol 21:1493PubMedCrossRefGoogle Scholar
  31. 31.
    Klijn JGM, de Jong FH, Lamberts SWJ, Blankenstein MA (1985) LHRH-agonist treatment in clinical and experimental human breast cancer. J Steroid Biochem 23:867PubMedCrossRefGoogle Scholar
  32. 32.
    Wiznitzer I, Benz L (1984) Direct growth inhibiting effects of the prolactin antagonist buserelin and pergolide on human breast cancer. Proc Am Assoc Cancer Res 25:208Google Scholar
  33. 33.
    Foekens JA, Henkelman MS, Fukkink JF, Blankenstein MA, Klijn JGM (1986) Combined effects of buserelin, estradiol and tamoxifen on the growth of MCF-7 human breast cancer cells in vitro. Biochem Biophys Res Commun 140:550PubMedCrossRefGoogle Scholar
  34. 34.
    Foekens JA, Henkelman MS, Bolt-de Vries J, Portengen H, Fukkink JF, Blankenstein MA, van Steenbrugge GJ, Mulder E, Klijn JGM (1987) Direct effects of LHRH analogs on breast and prostate tumor cells. In: Klijn JGM, Paridaens R, Foekens JA (eds) Hormonal manipulation of cancer: peptides, growth factors, and new (anti) steroidal agents. Raven, New York, p 369 (EORTC monograph series, vol 18)Google Scholar
  35. 35.
    Foekens JA, Klijn JGM (1988) Direct antitumor effects of an LH-RH agonist. In: Höffken K (ed) LH-RH agonists in oncology. Springer, Berlin Heidelberg New York, p22CrossRefGoogle Scholar
  36. 36.
    Sharoni Y, Bosin E, Münster A, Levy J, Serially AV (1989) Inhibition of growth of human mammary tumor cells by potent antagonists of luteinizing hormone-releasing hormone. Proc Natl Acad Sci USA 86:1648PubMedCrossRefGoogle Scholar
  37. 37.
    De Launoit Y, Kiss R, Danguy A, Paridaens R (1987) Effects of ovariectomy, hypophy-sectomy and/or GnRH analog (HRF) administration on the cell proliferation of the MXT mouse hormone-dependent mammary tumor. Eur J Cancer Clin Oncol 23:1443PubMedCrossRefGoogle Scholar
  38. 38.
    Furr BJA, Nicholson RI (1982) Use of analogs of luteinizing hormone-releasing hormone for the treatment of cancer. J Reprod Fert 64:529CrossRefGoogle Scholar
  39. 39.
    Nicholson RI, Walker KJ, Turkes A, Dyas J, Gotting KE, Plowman PM, Williams M, Elston CW, Blarney RW (1987). The British experience with the LH-RH agonist Zoladex (ICI 118630) in the treatment of breast cancer. In: Klijn JGM, Paridaens R, Foekens JA (eds) Hormonal manipulation of cancer: peptides, growth factors, and new (anti) steroidal agents. Raven, New York, p 331 (EORTC Monograph Series, vol 18)Google Scholar
  40. 40.
    Segal T, Levy J, Sharoni Y (1987) GnRH analogs stimulate phospholipase C activity in mammary tumor membranes: modulation by GTP. Mol Cell Endocrinol 53:239PubMedCrossRefGoogle Scholar
  41. 41.
    Wilding G, Chen M, Gelman EP (1987) LHRH agonists and human breast cancer cells. Nature 329:770PubMedCrossRefGoogle Scholar
  42. 42.
    Dowsett M, Cantwell B, Lal A, Jeffcoate SL, Harris AL (1988) Suppression of post-menopausal ovarian steroidogenesis with the luteinizing hormone-releasing hormone agonist goserelin. J Clin Endocrinol Metab 66:672PubMedCrossRefGoogle Scholar
  43. 43.
    Schally AV, Bajusz S, Redding TW, Zalatnai A, Comaru-Schally AM (1989) Analogs of LHRH: the present and the future. In: Vickery BH, Lunenfeld V (eds) GnRH analogues in cancer and human reproduction, vol 1, Basic aspects. Kluwer, Dordrecht, p 5Google Scholar
  44. 44.
    Schally AV, Srkalovic G, Szende B, Redding TW, Janaky T, Juhasz A, Korkut E, Cai RZ, Szepeshazi K, Radulovic S, Bokser L, Groot K, Serfozo P, Comaru-Schally AM (1990) Antitumor effects of anlogs of LH-RH and somatostatin: experimental and clinical studies. J Steoid Biochem Mol Biol 37:1061CrossRefGoogle Scholar
  45. 45.
    Schally AV, Redding TW (1987) Use of LH-RH analogs for the treatment of prostate cancer: combination therapy and direct effects. In: Klijn JGM, Paridaens R, Foekens JA (eds) Hormonal manipulation of cancer: peptides, growth factors, and new (anti) steroidal agents. Raven, New York, p 273 (EORTC Monograph Series, vol 18)Google Scholar
  46. 46.
    Schally AV, Redding TW, Paz-Bouza JI, Comaru-Schally AM, Mathé G (1987) Current consept for improving treatment of prostate cancer based on combination of LH-RH agonists with other agents. In: Murphy G, Küss R, Khoury S, Chátelain C, Denis L (eds) Prostate cancer part A: research endocrine treatment and histopathology. Liss, New York, p 173Google Scholar
  47. 47.
    Hierowski MT, Altamirano P. Redding TW, Schally AV (1983) The presence of LHRH-like receptors in Dunning R3327H prostate tumors. FEBS Lett 154:92PubMedCrossRefGoogle Scholar
  48. 48.
    Kadar T, Redding TW, Ben-David M, Schally AV (1988) Receptors for prolactin, somatostatin, and luteinizing hormone-releasing hormone in experimental prostate cancer after treatment with analogs of luteinizing hormone-releasing hormone and somatostatin. Proc Natl Acad Sci USA 85:890PubMedCrossRefGoogle Scholar
  49. 49.
    Fekete M, Redding TW, Comaru-Schally AM, Pontes JE, Connelly RW, Srkalovic G, Schally AV (1989) Receptors for luteinizing hormone-releasing hormone, somatostatin, prolactin, and epidermal growth factor in rat and human prostate cancers and in benign prostate hyperplasia. Prostate 14:191PubMedCrossRefGoogle Scholar
  50. 50.
    Kadar T, Ben-Davin M, Pontes JE, Fekete M, Dchally AV (1968) Prolactin and luteinizing hormone-releasing hormone receptors in human benign prostatic hyperplasia and prostate cancer. Prostate 12:299CrossRefGoogle Scholar
  51. 51.
    Scaletzky R, Qayum A, Clayton RN, Sikora K, Waxman J (1988) GnRH analogue and dihydrotestosterone treatment regulate expression of GnRH binding in a human hormone dependent prostatic cancer cell line. Gynecol Endocrinol 2 (Suppl 1): 100Google Scholar
  52. 52.
    Quayum A, Gullick WJ, Mellon K, Krausz T, Neal D, Sikora K, Waxman J (1990) The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines. J Steroid Biochem Mol Biol 37:899CrossRefGoogle Scholar
  53. 53.
    Lamberts SWJ, Timmers JM, Oosterom R, Verleun T, Rommerts FG, de Jong FH (1982) Testosterone secretion by cultured arrhenoblastoma cells: suppression by a luteinizing hormone-releasing hormone agonist. J Clin Endocrinol Metab 54:450PubMedCrossRefGoogle Scholar
  54. 54.
    Simon WE, Hölzel F (1979) Hormone sensitivity of gynecological tumor cells in tissue cultures. J Cancer Res Clin Oncol 94:307PubMedCrossRefGoogle Scholar
  55. 55.
    Simon WE, Albrecht M, Hänzel M, Dietel M, Hölzel F (1983) Cell Unes derived from human ovarian carcinomas: growth stimulation by gonadotropic hormones. J Natl Cancer Inst 70:839PubMedGoogle Scholar
  56. 56.
    Emons G, Pahwa GS, Ortmann O, Knuppen R, Oberheuser F, Schultz K-D (1990) LHRH-receptors and LHRH-agonist treatment in ovarian cancer. J Steroid Biochem Mol Biol 37:1003PubMedCrossRefGoogle Scholar
  57. 57.
    Rao BR, Slotman BJ (1991) Endocrine factors in common epithelial ovarian cancer. Endocr Rev 12:14PubMedCrossRefGoogle Scholar
  58. 58.
    Kullander S, Rausing A, Schally AV (1987) LHRH agonist treatment in ovarian cancer. In: Klijn JGM, Paridaens R, Foekens JA (eds) Hormonal manipulation of cancer: peptides, growth factors, and new (anti) steroidal agents. Raven, New York, p 353 (EORTC monograph series, vol 18)Google Scholar
  59. 59.
    Pour PM, Redding TW, Paz-Bouza JI, Schally AV (1988) Treatment of experimental ovarian carcinoma with monthly injection of the agonist D-Trp6-LH-RH: a preliminary report. Cancer Lett 41:105PubMedCrossRefGoogle Scholar
  60. 60.
    Mortel R, Satyaswaroop PG, Schally AV, Hamilton T, Ozols R (1986) Inhibitory effects of GnRH superagonist on the growth of human ovarian carcinoma NIH: OVCAR-3 in the nude mouse. Gynaecol Oncol 23:254CrossRefGoogle Scholar
  61. 61.
    Aten RF, Williams AT, Behrman HR (1986) Ovarian gonadotropin-releasing hormone-like protein(s): demonstration and characterization. Endocrinology 118:961PubMedCrossRefGoogle Scholar
  62. 62.
    Behrman HR, Preston SL, Hall AK (1980) Cellular mechanism of the antigonadotropic action of luteinizing hormone-releasing hormone in the corpus luteum. Endocrinology 107:656PubMedCrossRefGoogle Scholar
  63. 63.
    Jones PBC, Conn PM, Marian J, Hsueh AJW (1980) Binding of gonadotropin releasing hormone agonist to rat ovarian granulosa cell cells. Life Sci 27:2125PubMedCrossRefGoogle Scholar
  64. 64.
    Clayton RN, Harwood JP, Catt KJ (1979) Gonadotropin-releasing hormone analogue binds to luteal cells and inhibits progesterone production. Nature 282:90PubMedCrossRefGoogle Scholar
  65. 65.
    Hsueh AJW, Jones PBC (1981) Extrapituitary actions of gonadotropin-releasing hormone. Endocr Rev 2:437PubMedCrossRefGoogle Scholar
  66. 66.
    Aten RF, Polan ML, Bayless R, Behrman HR (1987) A gonadotropin-releasing hormone (GnRH)-like protein in human ovaries: similarity to the GnRH-like ovarian protein of the rat. J Clin Endocrinol Metab 64:1288PubMedCrossRefGoogle Scholar
  67. 67.
    Popkin R, Bramley TA, Currie A, Shaw RW, Baird DT, Frazer (1983). Specific binding of luteinizing hormone releasing hormone to human luteal tissue. Biochem Biophys Res Commun 114:750PubMedCrossRefGoogle Scholar
  68. 68.
    Bramley TA, Menzies GS, Baird DT (1985) Specific binding of gonadotropin-releasing hormone and an agonist to human corpus luteum homogenates: characterization, properties, and luteal phase levels. J Clin Endocrinol Metab 61:834PubMedCrossRefGoogle Scholar
  69. 69.
    Pahwa GS, Vollmer G, Knuppen R, Emons G (1989) Photoaffinity labelling of gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata. Biochem Biophys Res Commun 161:1086PubMedCrossRefGoogle Scholar
  70. 70.
    Emons G, Pahwa GS, Brack C, Sturm R, Oberhauser F, Knuppen R (1989) Gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata. Eur J Cancer Clin Oncol 25:215PubMedCrossRefGoogle Scholar
  71. 71.
    Parmar H, Phillips RH, Rustin G, Lightman SL, Schally AV (1988) Therapy of advanced ovarian cancer with D-Trp-6-LHRH (decapeptyl) microcapsules. Biomed Pharmacother 42:531PubMedGoogle Scholar
  72. 72.
    Slotman BJ, Poels LG, Rao BR (1989) A direct LHRH-agonist action on cancer cells is unlikely to be the case of response to LHRH-agonist therapy. Anticancer Res 9:77PubMedGoogle Scholar
  73. 73.
    Hsueh AJW, Schaeffer JM (1985) Gonadotropin-releasing hormone as a paracrine hormone and neurotransmitter in extra-pituitary sites. J Steroid Biochem 23:757PubMedCrossRefGoogle Scholar
  74. 74.
    Knecht M, Ranta T, Feng P, Shinohara O, Catt KJ (1985) Gonadotropin-releasing hormone as a modulator of ovarian function. J Steroid Biochem 23:771PubMedCrossRefGoogle Scholar
  75. 75.
    Parmar H, Nicoll J, Stockdale A, Cassoni A, Phillips RH, Lightman SL, Schally AV (1985) Advanced ovarian carcinoma: response to the agonist D-Trp-6-LH-RH. Cancer Treat Rep 69:1341PubMedGoogle Scholar
  76. 76.
    Parmar H, Phillips RH, Rustin G, Hanham IW, Schally AV, Lightman SL (1988) Response to D-Trp-6-LHRH (decapeptyl) microcapsules in advanced ovarian cancer. Br Med J 296:1229CrossRefGoogle Scholar
  77. 77.
    Srkalovic G, Wittliff JL, Schally AV (1990) Detection and partial characterization of receptors for [D-Trp6]-luteinizing hormone-releasing hormone and epidermal growth factor in human endometrial carcinoma. Cancer Res 50:1841PubMedGoogle Scholar
  78. 78.
    Krenning EP, Bakker WH, Breeman WAP, Koper JW, Kooij PPM, Ausema L, Lameris JS, Reubi JC, Lamberts SWJ (1989) Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet i: 242CrossRefGoogle Scholar
  79. 79.
    Lamberts SWJ, Bakker WH, Reubi J-C, Krenning EP (1990) Somatostatin-receptor imaging in the localization of endocrine tumors. N Engl J Med 323:1246PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • J. A. Foekens
    • 1
  • J. G. M. Klijn
    • 1
  1. 1.Division of Endocrine Oncology (Department of Medical Oncology)Dr. Daniel den Hoed Cancer CenterRotterdamThe Netherlands

Personalised recommendations