RT Journal Article
SR Electronic
T1 Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 613
OP 623
DO 10.1124/jpet.110.174375
VO 336
IS 3
A1 Theodora Katsila
A1 Evangelos Balafas
A1 George Liapakis
A1 Patrizia Limonta
A1 Marina Montagnani Marelli
A1 Konstantinos Gkountelias
A1 Theodore Tselios
A1 Nikolaos Kostomitsopoulos
A1 John Matsoukas
A1 Constantin Tamvakopoulos
YR 2011
UL http://jpet.aspetjournals.org/content/336/3/613.abstract
AB Gonadotropin-releasing hormone (GnRH) receptor agonists have wide clinical applications including the treatment of prostate cancer and endocrine disorders. However, such agonists are characterized by poor pharmacokinetic properties, often requiring repeated administration or special formulations. Therefore, the development of novel peptide analogs with enhanced in vivo stability could potentially provide therapeutic alternatives. The pharmacological evaluation of a bioactive peptide [Des-Gly10,Tyr5(OMe),d-Leu6,Aze-NHEt9]GnRH, analog 1, is presented herein and compared with leuprolide. Peptide stability was evaluated using mouse kidney membrane preparations, followed by a liquid chromatography-tandem mass spectrometry-based approach that afforded identification and quantification of its major metabolites. The analog was significantly more stable in vitro in comparison with leuprolide. In vitro and in vivo stability results correlated well, encouraging us to develop a clinically relevant pharmacokinetic mouse model, which facilitated efficacy measurements using testosterone as a biomarker. Analog 1, an agonist of the GnRH receptor with a binding affinity in the nanomolar range, caused testosterone release in mice that was acutely dose-dependent, an effect blocked by the GnRH receptor antagonist cetrorelix. Repeated dosing studies in mice demonstrated that analog 1 was well tolerated and had potency similar to that of leuprolide, based on plasma and testis testosterone reduction and histopathological findings. Analog 1 also shared with leuprolide similar significant antiproliferative activity on androgen-dependent prostate cancer (LNCaP) cells. On the basis of pharmacokinetic advantages, we expect that analog 1 or analogs based on this new design will be therapeutically advantageous for the treatment of cancer and endocrine disorders.