New LHRH antagonists with enhanced biological activity: Preclinical and clinical results

Gonadorelin (GnRH, LHRH) analogs are indispensable drugs for the clinical treatment of sex-hormone dependent tumors, such as breast, ovary and prostate cancer. LHRH agonists and antagonists have also been utilized in various artificial reproduction techniques and have been investigated as potential contraceptives in humans [1]. Over 25 years, thousands of analogs of LHRH, both agonists and antagonists, have been synthesized and evaluated for potential therapeutic benefit. Agonists, e.g. Leuprolide or Goserelin, are well established in medical treatment. They stimulate, initially and for several days, the release of LH and FSH prior to downregulation of the LHRH receptor, causing transiently rising levels of sexual steroid hormones testosterone and estradiol. Third generation antagonists like Cetrorelix, Abarelix, or Ganirelix are under investigation in clinical studies. Cetrorelix itself has been characterized as a safe and potent LHRH antagonist, based on results in a variety of models. Clinical studies indicate that Cetrorelix is a highly effective gonadotropineand subsequently sexsteroid-suppressing agent. Therefore, Cetrorelix has potential for treatment of hormone dependent cancers as well as for non-malignant applications in which a suppression or control of gonadotropins and sex-steroids is desired [2]. The advantage of Cetrorelix is that it inhibits LH and testosterone from the beginning of administration and thereby avoids the agonist-induced “flare up effect.” Treatment of prostatic carcinoma and pre-menopausal mammary carcinoma are primary applications. Endometriosis and benign prostate hyperplasia (BPH) also represent also attractive applications for the LHRH antagonist. Cetrorelix (Cetrotide®) has been approved in 1999 by EU authorities for marketing within the European Union for controlled ovulation stimulation for assisted reproduction (COS/ART).