Rapid Suppression of Plasma Testosterone Levels and Tumor Growth in the Dunning Rat Model Treated with Degarelix, a New Gonadotropin-Releasing Hormone Antagonist

Abstract

Degarelix (FE 200486) is a member of a new class of water-soluble (>50 mg/ml) gonadotropin-releasing hormone (GnRH) antagonists in clinical development for prostate cancer. Upon subcutaneous administration, degarelix forms a gel that results in a sustained release of the compound into the circulation, immediately blocking GnRH receptors in the pituitary and inducing a fast and sustained suppression of gonadotrophin secretion in rats and primates. One of the few animal models of prostate adenocarcinoma is the Dunning R-3327H rat carcinoma transplanted into Copenhagen rats. The growth of the Dunning tumor can be inhibited by various treatments reported to be effective in the clinic, such as GnRH superagonists, antiandrogens, 5-alphareductase inhibitors, tyrosine kinase inhibitors, and surgical castration. We report in this study that degarelix produces a fast and sustained suppression of the pituitary gonadal axis in rats and a similar inhibition of tumor growth compared with surgical castration in the Dunning R-3327H rat carcinoma model. First, degarelix as been compared with d-Trp(6)-luteinizing hormone-releasing hormone and surgical castration on a short-term study (2 months); and second, degarelix has been compared with leuprolide and surgical castration on a long-term study (12 months). In both studies, degarelix demonstrated a sustained inhibition of tumor growth at least comparable with surgical castration. These data provide a convincing profile of degarelix as a potential candidate for the clinical management of sex steroid-dependent pathologies, such as prostate cancer, where long-term reversible chemical castration is required.

The current abilities of third-generation luteinizing hormone-releasing hormone antagonists in the treatment of hormone-responsive prostate cancer

“…В ис-следовании на животных дегареликс имел самую низкую актив-ность в отношении высвобождения гистамина среди всех проте-стированных антагонистов ЛГРГ. На ex vivo модели человеческой кожи показаны аналогичные результаты: дегареликс демонстри-ровал самую низкую склонность к высвобождению гистамина по сравнению с ганиреликсом, абареликсом и цетрореликсом [31,32,[38][39][40].…”

Experience with degarelix in the treatment of prostate cancer

“…Subcutaneous administration of degarelix allows the formation of a gel depot that facilitates sustained drug release [Princivalle et al 2007]. This is reflected in the prolonged LH and testosterone suppression associated with degarelix which, in comparative studies, displayed a longer duration of action than other GnRH antagonists (abarelix, cetrorelix, ganirelix, azaline B).…”

Current Medical and Surgical Options for Androgen Deprivation in Prostate Cancer Patients

“…Initially, preclinical study in rats suggested that rapid, profound and sustained testosterone suppression achieved with degarelix might result in greater suppression of tumor growth than is achieved with GnRH-A [33,34]. Those promising results have led to phase II/III clinical studies.…”