Received for publication August 11, 2006.
Revised November 16, 2006.
Accepted for publication December 18, 2006.

Rapid suppression of plasma testosterone levels and tumor growth in the Dunning rat model treated with degarelix, a new GnRH antagonist

Abstract

Degarelix (FE 200486) is a member of a new class of water-soluble (>50 mg/ml) GnRH antagonists in clinical development for prostate cancer. Upon subcutaneous administration degarelix forms a gel resulting in a sustained release of the compound into the circulation immediately blocking GnRH receptors in the pituitary 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 R3327H rat carcinoma transplanted into Copenhagen rats. The growth of the Dunning tumour 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 tumour growth compared to surgical castration in the Dunning R3327H rat carcinoma model. Firstly, degarelix has been compared with D-Trp⁶-LHRH and surgical castration on a short-term study (2 months) and secondly, 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 tumour growth at least comparable to 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.

Key words: Cancer therapy, Dunning R3327H, GnRH antagonist, Prostate cancer, degarelix, in vivo model