Will GnRH antagonists improve prostate cancer treatment?

Huhtaniemi, Ilpo; White, Richard; McArdle, Craig A.; Persson, Bo‐Eric

doi:10.1016/j.tem.2008.09.003

Cited by 47 publications

(33 citation statements)

References 75 publications

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“…Although several antagonists have been investigated in recent years, only degarelix and abarelix are currently available for clinical use in PCa. Moreover, abarelix has been associated with the risk of systemic allergic reactions and, although currently available in Germany, was withdrawn in the US in 2005 [Huhtaniemi et al 2009]. By contrast, degarelix, the first of a new generation of GnRH antagonists, has been shown in an extensive clinical development programme to retain the efficacy benefits of these agents without the systemic allergic reactions associated with the earlier members of the class.…”

Section: Discussionmentioning

confidence: 99%

An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer

Boccon-Gibod

Meulen

Persson

2011

Therapeutic Advances in Urology

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Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of gonadotropin-releasing hormone (GnRH) agonists. However, despite their efficacy, GnRH agonists have several drawbacks associated with their mode of action. These include an initial testosterone surge and testosterone microsurges on repeat administration. GnRH antagonists provide an alternative approach to ADT with a more direct mode of action that involves immediate blockade of GnRH receptors. Antagonists produce a more rapid suppression of testosterone (and prostatespecific antigen [PSA]) without a testosterone surge or microsurges and appear to offer an effective and well tolerated option for the hormonal treatment of prostate cancer. Comparisons with GnRH agonists have shown GnRH antagonists to be at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. Furthermore, with antagonists, the lack of an initial testosterone surge (which may cause clinical flare) may allow more rapid relief of symptoms related to prostate cancer, avoid the need for concomitant antiandrogens to prevent clinical flare (so avoiding any antiandrogen-associated adverse events) and allow GnRH antagonist use in patients with high tumour burden and/or acute problems such as spinal cord compression. Although several antagonists have been investigated, only degarelix and abarelix are currently available for clinical use in prostate cancer. Currently, degarelix is the most extensively studied and widely available agent in this class. Degarelix is one of a newer generation of antagonists which, in a comprehensive and ongoing clinical development programme, has been shown to provide rapid, profound and sustained testosterone suppression without the systemic allergic reactions associated with earlier antagonists. This review examines the currently available data on GnRH antagonists in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer

Boccon-Gibod

Meulen

Persson

2011

Therapeutic Advances in Urology

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“…Like GnRH agonists, these agents prevent testicular androgen synthesis, but fail to induce the transient testosterone flare associated with GnRH agonists (38, 39). Administration or use of first generation GnRH antagonists such as abarelix was limited by untoward side effects (27, 40), but recent modifications to the structure of the product resulted in reduced immunostimulatory activity and safer administration (41).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer

Knudsen

Scher

2009

Clinical Cancer Research

273

280

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Clinical data and models of human disease indicate that androgen receptor (AR) activity is essential for prostate cancer development, growth, and progression. The dependence of prostatic adenocarcinoma on AR signaling at all stages of disease has thereby been exploited in the treatment of disseminated tumors, for which ablation of AR function is the goal of first-line therapy. Although these strategies are initially effective, recurrent tumors arise with restored AR activity, and no durable treatment has yet been identified to combat this stage of disease. New insights into AR regulation and the mechanisms underlying resurgent AR activity have provided fertile ground for the development of novel strategies to more effectively inhibit receptor activity and prolong the transition to therapeutic failure.

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“…Desensitization is clinically exploited by all GnRH receptor agonists (buserelin, goserelin, leuprolide, and triptorelin), however, mammalian GnRH receptors lack the C-terminus implying that the desensitization process differs from the large majority of GPCRs [67] and/or the molecular mechanisms responsible for this complex phenomenon still awaits full clarification.…”

Section: Gpcrs Desensitizationmentioning

confidence: 99%

Molecular Approaches To Target GPCRs in Cancer Therapy

et al. 2011

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Hundreds of G protein coupled receptor (GPCR) isotypes integrate and coordinate the function of individual cells mediating signaling between different organs in our bodies. As an aberration of the normal relationships that organize cells' coexistence, cancer has to deceive cell-cell communication in order to grow and spread. GPCRs play a critical role in this process. Despite the fact that GPCRs represent one of the most common drug targets, current medical practice includes only a few anticancer compounds directly acting on their signaling. Many approaches can be envisaged to target GPCRs involved in oncology. Beyond interfering with GPCRs signaling by using agonists or antagonists to prevent cell proliferation, favor apoptosis, induce maturation, prevent migration, etc., the high specificity of the interaction between the receptors and their ligands can be exploited to deliver toxins, antineoplastic drugs or isotopes to transformed cells. In this review we describe the strategies that are in use, or appear promising, to act directly on GPCRs in the fight against neoplastic transformation and tumor progression.

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Will GnRH antagonists improve prostate cancer treatment?

Cited by 47 publications

References 75 publications

An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer

An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer

Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer

Molecular Approaches To Target GPCRs in Cancer Therapy

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