Luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer: A review of their discovery, development, and place in therapy

Moreau, Jacques-Pierre; Delavault, Patrick; Blumberg, Joëlle

doi:10.1016/j.clinthera.2006.10.018

Cited by 68 publications

(44 citation statements)

References 97 publications

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“…This was in line with the previous studies showing that the kidney plays an important role in the metabolism of LHRH derivatives (39,40). The native LHRH is degraded rapidly in blood and has a short half-life of 3-4 min (36). We showed that compounds 1 and 6 remained intact in the human plasma during the 4-h incubation.…”

Section: Discussionsupporting

confidence: 79%

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Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

Moradi

Varamini

Tóth

2015

AAPS J

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Abstract. The enzymatic stability, antitumor activity, and gonadotropin stimulatory effects of glycosylated luteinizing hormone-releasing hormone (LHRH) analogs were investigated in this study. Conjugation of carbohydrate units, including lactose (Lac), glucose (GS), and galactose (Gal) to LHRH peptide protected the peptide from proteolytic degradation and increased the peptides' half-lives in human plasma, rat kidney membrane enzymes, and liver homogenate markedly. Among all seven modified analogs, compound 1 (]LHRH) and compound 6 (GS 4 -[w 6 ]LHRH) were stable in human plasma during 4 h of experiment. The half-lives of compounds 1 and 6 improved significantly in kidney membrane enzymes (from 3 min for LHRH to 68 and 103 min, respectively). The major cleavage sites for most of the glycosylated compounds were found to be at Trp ]LHRH) stimulated the release of follicle-stimulating hormone (FSH) at 5 nM concentration in dispersed rat pituitary cells (p<0.05). In our studies, compound 1-bearing lactose and D-Trp was the most stable and active and is a promising candidate for future preclinical investigations in terms of in vitro biological activity and metabolic stability.

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Section: Discussionsupporting

confidence: 79%

“…The therapeutic benefits of LHRH derivatives have been proven in the treatment of hormone-dependent diseases (36,37). However, all agonists and antagonists of LHRH are characterized by poor pharmacokinetic properties when they are orally administered.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

Moradi

Varamini

Tóth

2015

AAPS J

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“…Androgen deprivation therapy (ADT) remains the most effective therapy for men with advanced disease, and although up to 80% show initial response, castrationresistant prostate cancer (CRPC) progression almost invariably occurs within 24 months. Androgen ablation induces apoptosis in subpopulations of PCa cells, but despite high initial response rates, remissions are temporary because surviving tumor cells usually recur with an AI phenotype (3)(4)(5). CRPC progression is a complex process by which cells acquire the ability to both survive and proliferate in the absence of androgens and involves variable combinations of clonal selection, adaptive upregulation of anti-apoptotic genes, and alternative growth factor pathways (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo

Thomas

Zoubeidi

Kuruma

et al. 2011

Molecular Cancer Therapeutics

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Signal transducer and activator of transcription 5 (Stat5) plays an important role in the transition of prostate cancer (PCa) to its castrate-resistant state. Pharmacologic targeting of Stat5 is a rational approach to delay castrate-resistant progression, in part, because Stat5 cooperates with the androgen receptor (AR) to promote PCa progression. Immunostaining of tissue microarrays was used to correlate Stat5 expression with Gleason grade and to characterize changes in treatment-naive and androgen-deprived human PCa. Potency of a Stat5 antisense oligonucleotide (ASO) on Stat5 knockdown, cell growth, and apoptosis was assessed in LNCaP, C4-2, and DU145 cells. Effects of Stat5 knockdown on AR activity and stability was assessed using a PSA transactivation-luciferase assay and cyclohexamide plus MG132 treatment, respectively. LNCaP tumorbearing mice were castrated and randomly assigned to treatment with Stat5-ASO or controls. Here, we show that the frequency of Stat5 expression is significantly increased in high Gleason grade as well as in hormone-treated PCa. Also, specific knockdown of Stat5 with ASO abrogates androgen-induced AR nuclear translocation and PSA transactivation despite R1881 stimulation. Moreover, Stat5 knockdown destabilizes AR, which leads to AR degradation via the proteasome. Shown for the first time as a preclinical proof-ofprinciple, Stat5 knockdown with Stat5-ASO significantly delays CRPC tumor progression in vivo. Thereby, we are able to recapitulate our in vitro results by reducing serum PSA and expression levels of target proteins in the xenograft tumors. Mol Cancer Ther; 10(2); 347-59. Ó2011 AACR.

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“…Since the amino acid sequence elucidation of LHRH (Figure 1) by Schally et al in 1971 [8], thousands of LHRH analogues have been synthesized with the aim of increasing the stability and bioavailability of the peptide [7]. Substitution of the amino acids in positions 6 and 10 of the LHRH sequence was found to enhance the stability of the LHRH derivatives [6].…”

Section: Introductionmentioning

confidence: 99%

“…Native LHRH has a short half-life of approximately 3 -4 minutes in human blood, resulting from enzymatic degradation of the peptide, mainly at positions 6 and 10 of the LHRH sequence [7]. Since the amino acid sequence elucidation of LHRH (Figure 1) by Schally et al in 1971 [8], thousands of LHRH analogues have been synthesized with the aim of increasing the stability and bioavailability of the peptide [7].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Luteinizing Hormone-Releasing Hormone (LHRH)-Functionalized Mini-Dendrimers

Rafiee¹,

Mansfeld²,

Moyle³

et al. 2013

IJOC

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Luteinizing hormone-releasing hormone (LHRH) is the key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, which is responsible for the development and functioning of the reproductive system. Delivery of a continuous supply of LHRH agonists causes down-regulation of the LHRH receptors, resulting in a marked decrease in androgens in males and estrogens in females. LHRH analogues are widely used in the treatment of various diseases, including prostate and breast cancer, and reproductive disorders, such as infertility and precocious puberty. However, they require parenteral administration, and no oral formulations are currently available. We synthesized two types of LHRH mini-dendrimers using thioether ligation, aiming to enhance the stability and bioavailability of the peptide drug while maintaining its biologically active conformation. These two compounds include a poly-lysine core conjugated to either the C-terminus of LHRH or a D-amino acid in position 6 of the LHRH sequence. The synthesized dendrimers were analysed using dynamic light scattering, and showed particle sizes of 155 and 115 nm, respectively. The nanometer size, well-defined structure and water solubility of these dendritic analogues make them excellent candidates for further exploration in oral peptide drug delivery.

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Luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer: A review of their discovery, development, and place in therapy

Cited by 68 publications

References 97 publications

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

Transcription Factor Stat5 Knockdown Enhances Androgen Receptor Degradation and Delays Castration-Resistant Prostate Cancer Progression In vivo

Synthesis and Characterization of Luteinizing Hormone-Releasing Hormone (LHRH)-Functionalized Mini-Dendrimers

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