Agonists of luteinizing hormone-releasing hormone in prostate cancer

Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, South Florida Veterans Affairs Foundation for Research and Education , 1201 NW 16th St, Research (151), Room 2A103C, Miami, FL 33125 , USA +1 305 575 3477
Expert Opinion on Pharmacotherapy (Impact Factor: 3.53). 08/2013; 14(16). DOI: 10.1517/14656566.2013.834328
Source: PubMed


Androgen deprivation therapy (ADT) has been the first-line standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for many decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT.

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This article reviews the available data and most recent information concerning the use of LHRH agonists in advanced PCa. This article also reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PCa.

Expert opinion:
The introduction and application of agonists of LHRH has modernized and improved the treatment of advanced PCa. The life-saving benefits of LHRH agonists are well established, yet underestimated. Despite their efficacy, agonists of LHRH have several disadvantages or drawbacks including disease flare. The approach to ADT has been recently further refined with the development of the LHRH antagonist degarelix. Degarelix, a highly clinically effective third-generation LHRH antagonist, is currently available in most countries for therapy of advanced PCa. This new drug offers attractive alternatives to LHRH agonists for treatment of advanced PCa. A therapy for castration-resistant PCa based on a targeted cytotoxic analog of LHRH, AEZS-108, is also emerging.

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    • "In 2014, prostate cancer is expected to account for 27% of newly detected cancers and 10% of cancer-related deaths in men in the US [1]. Standard therapy of metastatic prostate cancer is androgen deprivation therapy (ADT) currently achieved by surgical orchiectomy or by treatment with LHRH agonist or antagonist [2-4]. Continuous administration of LHRH analogs downregulates pituitary LHRH receptors thus leading to the suppression of gonadotropin (luteinizing hormone and follicle-stimulating hormone) release and a consequent drop in production of gonadal androgens [2, 5]. "
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    ABSTRACT: Management of castration-resistant prostate cancer (CRPC) is challenging due to lack of efficacious therapy. Luteinizing hormone-releasing hormone analogs appear to act directly on cells based on the LHRH receptors on human prostate adenocarcinoma cells. We explored anticancer activity of a cytotoxic analog of LHRH, AEZS-108 consisting of LHRH agonist linked to doxorubicin. Nude mice bearing DU-145 tumors were used to compare antitumor effects of AEZS-108 with its individual constituents or their unconjugated combination. The tumor growth inhibition of conjugate was greatest among treatment groups (90.5% inhibition vs. 41% by [D-Lys(6)]LHRH+DOX). The presence of LHRH receptors on DU-145 cells was confirmed by immunocytochemistry. In vitro, AEZS-108 significantly inhibited cell proliferation (61.2% inhibition) and elevated apoptosis rates (by 46%). By the detection of the inherent doxorubicin fluorescence, unconjugated doxorubicin was seen in the nucleus; the conjugate was perinuclear and at cell membrane. Autophagy, visualized by GFP-tagged p62 reporter, was increased by AEZS-108 (7.9-fold vs. 5.3-fold by DOX+[D-Lys(6)]LHRH. AEZS-108 more effectively increased reactive oxygen species (ROS, 2-fold vs. 1.4-fold by DOX+[D-Lys(6)]LHRH) and levels of the apoptotic regulator p21 in vivo and in vitro. We demonstrate robust inhibitory effects of the targeted cytotoxic LHRH analog AEZS-108 on LHRHR positive castration-resistant prostate cancer cells.
    Full-text · Article · Jun 2014 · Oncotarget
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    ABSTRACT: The most common form of hormonal treatment for prostate cancer is luteinizing hormone-releasing hormone (LHRH)-agonist therapy. During the first 1 to 3 weeks of LHRH-agonist therapy, an initial increase in testosterone is associated with a condition known as "flare." Blockade of flare can be accomplished with a number of agents, including flutamide, bicalutamide, nilutamide, diethylstilbestrol, ketoconazole, and cyproterone acetate. Evidence from the early use of LHRHagonists suggested that flare could be serious in nature, with an exacerbation of pain, increase in uremia, development of neurologic sequelae, and possibly death. These events have been uncommonly reported of late, most probably owing to the use of flare blockade in most patients with advanced disease, as well as the fact that many patients are currently being treated with much earlier disease. Evidence is conflicting as to whether flare makes a difference in less advanced disease. A few reports have noted complications during flare in patients in whom a blockade of flare was not required, including two deaths from one institution. Reported series, however, seem to suggest that with flare blockade, acute complications are extremely uncommon. Evidence suggests that 1) advanced disease should be blocked; 2) blockade should probably include an antiandrogen beginning about 1 week prior to administration of the LHRH-agonist; and 3) that patients without advanced disease but with very high PSA levels should be considered for flare blockade.
    Preview · Article · Feb 2001 · Reviews in urology
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    ABSTRACT: Although the mechanism behind the role of circulating androgens in the development and progression of prostatic carcinoma is not totally clear, androgen deprivation therapy remains a mainstay of treatment for this cancer. As surgical orchiectomy has fallen out of favor and the use of estrogens has been associated with cardiac toxicity, pharmacologic approaches have become even more common, namely, the use of luteinizing hormone-releasing hormone (LHRH) agonists. These agents, however, are not without side effects; the primary ones are the "flare" phenomenon, which stems from an initial surge in testosterone level and can include increased pain at metastatic sites, spinal cord compression, and even sudden death. Some studies have reported increased morbidity with the use of LHRH agonists, and while the significance of flare is not entirely known at this point, data seem to indicate that, at least in men with advanced disease, avoiding flare may be prudent.
    Preview · Article · Feb 2004 · Reviews in urology
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