Luteinizing Hormone-Releasing Hormone and Its Agonistic, Antagonistic, and Targeted Cytotoxic Analogs in Prostate Cancer

Abstract

Chronic administration of luteinizing hormone-releasing hormone I (LHRH-I) or its agonistic analogs leads to downregulation of pituitary receptors for LHRH, and a gradual suppression of circulating levels of gonadotropins and sex steroids. The creation of a state of sex-hormone deprivation produced by periodic administration of sustained delivery system of LHRH agonists forms the basis of therapy for advanced prostate cancer and other malignant neoplasms. LHRH antagonists developed in recent decades bind competitively to LHRH receptors and cause an immediate inhibition of the release of gonadotropins and sex steroids. This rapid induction of sex-hormone deprivation by LHRH antagonists makes them useful for the treatment of prostate cancer and other sex steroid-dependent cancers. Potent LHRH-I antagonists are finding important clinical applications in urology, oncology, and gynecology. In addition to their suppressive effects on sex-hormone secretion induced by the downregulation of pituitary LHRH receptors, LHRH agonists and antagonists also exert direct inhibitory actions on tumors, which are mediated by tumoral LHRH receptors. These direct actions contribute to the therapeutic effects of LHRH analogs on cancers and in the case LHRH-I antagonists are also utilized for the treatment of benign prostatic hyperplasia (BPH). In this chapter, we review some selected endocrine and antitumoral effects of LHRH agonists and antagonists and clinical trials on prostate cancer and BPH. Experimental studies and early clinical trials with targeted cytotoxic LHRH analogs developed recently for targeted chemotherapy of tumors expressing LHRH receptors are also described.