Development of GnRH Antagonists for Prostate Cancer: New Approaches to Treatment

Abstract

Prostate cancer has become the most common cancer among American men and is second only to lung cancer as a cause of male cancer‐related death. Several treatment options exist for different stages of prostate cancer including observation, prostatectomy, radiation therapy, chemotherapy, and hormone therapy. Hormone therapy has evolved from the use of estrogens to gonadotropin‐releasing hormone (GnRH) agonists and recently, investigational GnRH antagonists. GnRH receptor agonists such as leuprolide, bruserelin and goserelin have been used for the treatment of prostate cancer. These agonists eventually cause the inhibition of lutenizing hormone production, which in turn causes a suppression of testosterone and dihydrotestosterone, on which continued growth of prostate cancer cells depend. Several comparative studies of leuprorelin administered as daily injections or monthly depot injections have been reported. Disease progression was prevented in more than 72% of men administered daily leuprorelin, and in 82% to 89% of those receiving monthly depots. Another synthetic GnRH analog, goserelin, has been studied in a similar population of men with daily injections producing partial responses in 60% to 80% of men with previously untreated prostate cancer. Abarelix, a peptide antagonist of GnRH receptor, is also being studied for the treatment of prostate cancer. The discovery and development of GnRH antagonists may provide an important advance for patients with prostate cancer. Clearly the studies described herein, as well as many others, outline an exciting era of research to define the optimal use of hormonal therapy in prostate cancer.

A Gonadotropin-Releasing Hormone-II Antagonist Induces Autophagy of Prostate Cancer Cells

“…These GnRH analogues down-regulate or antagonize the GnRH receptor in the pituitary, thus causing a substantial decrease in serum gonadotropin and androgen levels (4)(5)(6). Although these pituitarymediated GnRH actions are useful only for androgen-dependent prostate cancer, GnRH-I also has direct actions on both androgendependent and androgen-independent prostate cancer cells.…”

Pharmacological Profile of a New, Potent, and Long-Acting Gonadotropin-Releasing Hormone Antagonist: Degarelix

“…The aim of the present study was to characterize the in vitro and in vivo pharmacological profile of a selected representative of this series, degarelix (FE200486: Ac-D-2Nal-D-4Cpa-D3Pal-Ser-4Aph (L-hydroorotyl)-D-4Aph (carbamoyl)-Leu-IlysPro-D-Ala-NH 2 ) in comparison with other recently developed GnRH antagonists such as abarelix (Cook and Sheridan, 2000), ganirelix (Gillies et al, 2000), cetrorelix (Reissmann et al, 2000), and azaline B (Rivier et al, 1995b). and were given free access to food and water.…”

Structure–Function Studies of Linear and Cyclized Peptide Antagonists of the GnRH Receptor

“…Antagonists have reached the market late with Cetrorelix (Cetrotide, ASTA Medica AG) or Ganirelix (Orgalutran; NV Organon) now used clinically in assisted fertilization protocols and Abarelix developed by Amgen Inc. for treatment of prostate cancer (12,25,26). Although many GnRH analogs were synthesized, systematic studies evaluating receptor binding and antagonistic potency toward different GnRH receptor proteins and the relevance of these parameters for efficacy in animal models are rare (27,28).…”