PTU - Polskie Towarzystwo Urologiczne
list of articles:

LHRH antagonist � new way of hormonal treatment of prostate cancer
Article published in Urologia Polska 2006/59/1.

authors

Jakub Dobruch, Andrzej Borówka
Klinika Urologii Centrum Medycznego Kształcenia Podyplomowego, I Zespół Dydaktyki Urologicznej - Oddział Urologii Międzyleskiego Szpitala Specjalistycznego w Warszawie

keywords

prostate, prostate cancer, hormonal treatment, LHRH antagonists

summary

Prostate cancer (PCa) cells are well known to be androgen dependent. Stopping androgen stimulation is basic method of advanced PCa treatment. There are three major methods of androgen deprivation in prostate cancer patients: a) orchiectomy (surgical castration), b) stopping gonadotropin secretion by means of pharmacological influence on hypophysis (pharmacological castration) and c) blocking androgen receptors. Widely used LHRH agonists cause pharmacological castration through LHRH receptors stimulation.
A recently introduced new form of hormonal treatment involved blocking LHRH receptors. LHRH antagonists combine with LHRH receptors located within hypophysis and influence its activity. The biochemical and endocrine efficiency of abarelix, one of LHRH antagonists, was explored in studies which involved prostate cancer patients who required hormonal therapy. It was then compared with LHRH agonists. There were no "flare-ups" in patients who received abarelix. Administration of LHRH antagonists was also associated with a decrease in FSH plasma concentration. FSH is suggested to induce prostate cancer androgen independence. In the present paper LHRH antagonists are described in detail with special emphasis on prostate cancer treatment.

references

  1. 1. Denmeade SR, Lin XS, Issacs JT: Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate 1996, 28, 251-265.
  2. 2. Nakada SY, di Sant?Agnese PA, Moynes RA et al: The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Res 1993, 53, 1967-1970.
  3. 3. Bruchovsky N, Rennie PS, Batzold FH et al: Kinetic parameters of 5a-reductase activity in stroma and epithelium of normal, hyperplastic, and carcinomatous human prostates. J Clin Endocrinol Metab 1988, 67, 806-816.
  4. 4. Rennie PS, Bruchovsky N: In vitro and in vivo studies on the functional significance of androgen receptors in rat prostate. J Biol Chem 1972, 247, 1546-1543.
  5. 5. Wilson EM, French FS: Binding properties of androgen receptors. Evidence for identical receptors in the rat testes, epididymis, and prostate. J Biol Chem 1978, 251, 5620-5629.
  6. 6. Coffey DS, Walsh PC: Clinical and experimental studies in benign prostatic hyperplasia. Urol Clin North Am 1990, 17, 461-476.
  7. 7. Denis L: Prostate cancer. Primary hormonal treatment. Cancer 1993, 71, 1050-1058.
  8. 8. Huggins C, Stevens RE, Hodges CV: Studies on prostatic cancer: the effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941, 43, 203-210.
  9. 9. Arcadi JA: Rapid drop in serum testosterone after bilateral subcapsular orchiectomy. J Surg Oncology 1992, 49, 35-38.
  10. 10. Trachtenberg J, Gittleman M, Steidle C et al: A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol 2002, 167, 1670-1674.
  11. 11. The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Eng J Med. 1984, 311, 1281-1286.
  12. 12. Thompson IM, Zeidman EJ, Rodriguez FR: Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol 1990, 144, 1479-1480.
  13. 13. Kuhn JM, Billebaud T, Navratil H et al: Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Eng J Med 1989, 321, 413-418.
  14. 14. Bubley GJ: Is the flare phenomenon clinically significant? Urol 2001, 58 (2 Suppl. 1), 5-9.
  15. 15. Fernandez del Moral P, Dijkman GA, Debruyne FM et al: Three-month depot of goserelin acetate: clinical efficacy and endocrine profile. Dutch South East Cooperative Urological Group. Urol 1996, 48, 894-900.
  16. 16. Borówka A, Siedlecki P: Nowotwory układu moczowo-płciowego, w: Zalecenia postępowania diagnostyczno-terapeutycznego w nowotworach złośliwych u dorosłych. Red: Krzakowski M. Polska Unia Onkologii. Warszawa 2003, 225-277.
  17. 17. Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997, 79, 235-246.
  18. 18. Nestor JJ Jr, Tahilramani R, Ho TL et al: Potent gonadotropin releasing hormone antagonists with low histamine-releasing activity. J Medicinal Chem 1992, 35, 3942-8394.
  19. 19. Huirne JA, Lambalk CB: Gonadotropin-releasing-hormone-receptor antagonist. Lancet 2001, 358, 1793-1803.
  20. 20. Fluker MR: Gonadotropin-releasing hormone antagonists. Curr Opin Endocrinol Diabetes 2000, 7, 350-356.
  21. 21. Wong SL, Lau DT, Baughman SA, et al: Pharmacokinetics and pharmacodynamics of abarelix, a gonadotropin-releasing hormone antagonist, after subcutaneous continous infusion in patients with prostate cancer. Clin Pharmacol Ther 2003, 73, 304-311.
  22. 22. Tomera K, Gleason D, Gittleman M et al: The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J Urol 2001, 165, 1585-1589.
  23. 23. Praecis Pharmaceuticals Symposium: ABACAS Study. XIX European Association of Urology annual meeting, Wiedeń, Austria, Marzec 2004 ? M. Garnick.
  24. 24. Mongiat-Artus P, Teillac P: Abarelix: The first gonadotrophin-releasing hormone antagonist for the treatment of prostate cancer. Expert Opinion Pharmacotherapy 2004, 5, 2171-2179.
  25. 25. Hurkadli KS, Sheth AR, Garde SV et al: Immunocytochemical localisation of follicle stimulating hormone (FSH) in normal, benign and malignant human prostates. Br J Cancer 1990, 61, 225-229.
  26. 26. Garde SV, Sheth AR, Shah MG, Kulkarni SA: Prostate ? an extrapituitary source of follicle-stimulating hormone (FSH): occurrence, localization, and de novo biosynthesis and its hormonal modulation in primates and rodents. Prostate 1991, 18, 271-287.
  27. 27. Ben-Josef E, Yang SY, Ji TH et al: Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). J Urol 1999, 161, 970-976.
  28. 28. Beer TM, Garzotto M, Eilers KM, Lemmon D: Phase II study of abarelix depot for androgen independent prostate cancer progression during gonadotropin-releasing hormone agonist therapy. J Urol 2003,169, 1738-1741.
  29. 29. Mahler C, Verhelst J, Chaban M, Denis L: Prolactin and pituitary gonadotropin values and responses to acute luteinizing hormonereleasing hormone (LHRH) challenge in patients having long term treatment with a depot LHRH analogue. Cancer 1991, 67: 557-559.
  30. 30. McLeod D, Zinner N, Tomera K: A Phase III, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urol 2001, 58, 756-761.
  31. 31. Bracci U, Di Silverio F, Sciarra F et al: Hormonal pattern in prostatic carcinoma following orchidectomy: 5-year follow-up. Br J Urol 1977, 49, 161-166.
  32. 32. Huhtaniemi IT, Dahl KD, Rannikko S, Hsueh AJW: Serum bioactive and immunoreactive follicle-stimulating hormone in prostatic cancer patients during gonadotropin-releasing hormone agonist treatment and after orchidectomy. J Clin Endocrinol Metab 1988, 66, 308-313.
  33. 33. Beer TM, Garzotto M, Eilers KM: Targeting FSH in androgen-independent prostate cancer: abarelix for prostate cancer progressing after orchiectomy. Urology 2004, 63, 342-347.
  34. 34. Koch M, Steidle C, Brosman S et al: An open-label study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists. Urology 2003, 62, 877-882.
  35. 35. Mongiat-Artus P, Teillac P: Abarelix: the first gonadotropin-releasing hormone antagonist for the treatment of prostate cancer. Expert Opinion Pharmacotherapy 2004, 5, 2171-2179.

correspondence

Jakub Dobruch
Oddział Urologii Międzyleskiego Szpitala Specjalistycznego
ul. Bursztynowa 2
04-749 Warszawa
tel. 0 503 072 230
kubadobr@amwaw.edu.pl