Degarelix

Degarelix is a synthetic peptide gonadotropin-releasing hormone (GnRH; IC₅₀=3nM) receptor antagonist. Degarelix reversibly binds to pituitary GnRH receptors, thereby inhibiting the release of gonadotropins^[1-2]. Degarelix is widely utilized in research related to the treatment of advanced prostate cancer^[3-4].

In vitro, treatment of various human prostate cell lines (including normal stromal WPMY-1, normal epithelial WPE1-NA22, benign hyperplastic BPH-1, androgen-dependent LNCaP, and castration-resistant VCaP cells) with Degarelix (0.1–10μM) for 24 to 72 hours, Degarelix significantly inhibited cell viability and induced apoptosis^[5]. Treatment of primary BPH epithelial and stromal cells (cultured alone or in co-culture) with Degarelix (5–30μM) for 24 to 72 hours, Degarelix significantly reducted cell viability and proliferation, activated of caspase 3/7^[6].

In vivo, in a PTEN/p53-deficient genetically engineered mouse model of prostate cancer, treatment with Degarelix (0.625mg per mouse; subcutaneous injection; once every 28 days) in combination with Copanlisib (14mg/kg; intravenous injection; every other day) and an anti-PD-1 antibody (200μg per mouse; intraperitoneal injection; every other day) for 28 days, Degarelix significantly reduced serum testosterone to castration levels. Degarelix significantly increased the proportion of the MHC-II^hi/PD-1^lo subpopulation of tumor-associated macrophages (TAMs) and enhanced their phagocytic activity^[7]. In low-density lipoprotein receptor knockout (LDLR^−/−) mice, following 4 months of treatment with Degarelix (50mg/kg; subcutaneous injection; once every 2 weeks), the mice exhibited reduced visceral fat accumulation, improved glucose tolerance, induced the least atherosclerotic plaque area and necrotic core area^[8].

References:
[1] Doehn C, Sommerauer M, Jocham D. Degarelix and its therapeutic potential in the treatment of prostate cancer. Clin Interv Aging. 2009;4:215-23.
[2] Steinberg M. Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer. Clin Ther. 2009;31 Pt 2:2312-31.
[3] Frampton JE, Lyseng-Williamson KA. Degarelix. Drugs. 2009 Oct 1;69(14):1967-76.
[4] Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8.
[5] Sakai M, Martinez-Arguelles DB, Patterson NH, et al. In search of the molecular mechanisms mediating the inhibitory effect of the GnRH antagonist degarelix on human prostate cell growth. PLoS One. 2015 Mar 26;10(3):e0120670.
[6] Sakai M, Elhilali M, Papadopoulos V. The GnRH Antagonist Degarelix Directly Inhibits Benign Prostate Hyperplasia Cell Growth. Horm Metab Res. 2015 Nov;47(12):925-931.
[7] Chaudagar K, Hieromnimon HM, Khurana R, et al. Reversal of Lactate and PD-1-mediated Macrophage Immunosuppression Controls Growth of PTEN/p53-deficient Prostate Cancer. Clin Cancer Res. 2023 May 15;29(10):1952-1968.
[8] Hopmans SN, Duivenvoorden WC, Werstuck GH, et al. GnRH antagonist associates with less adiposity and reduced characteristics of metabolic syndrome and atherosclerosis compared with orchiectomy and GnRH agonist in a preclinical mouse model. Urol Oncol. 2014 Nov;32(8):1126-34.

Degarelix是一种合成肽类促性腺激素释放激素（GnRH；IC₅₀=3nM）受体拮抗剂，Degarelix通过可逆地结合垂体GnRH受体，抑制促性腺激素的释放^[1-2]。Degarelix被广泛运用于晚期前列腺癌的治疗的相关研究^[3-4]。

在体外，Degarelix（0.1-10μM）处理多种人前列腺细胞系（包括正常基质WPMY-1、正常上皮WPE1-NA22、良性增生BPH-1、雄激素依赖型LNCaP和去势抵抗型VCaP细胞）24至72小时，Degarelix显著抑制细胞活力并诱导凋亡^[5]。Degarelix（5–30μM）处理原代BPH上皮与基质细胞（单独或共培养）24至72小时，Degarelix显著降低细胞活力与增殖，并激活caspase 3/7^[6]。

在体内，在PTEN/p53缺陷前列腺癌基因工程小鼠模型中，Degarelix（0.625mg/只；皮下注射；每28天一次）联合Copanlisib（14mg/kg；静脉注射;隔日一次）和抗PD-1抗体（200μg/只；腹腔注射；隔日一次）治疗28天，Degarelix显著降低血清睾酮至去势水平，Degarelix显著增加肿瘤相关巨噬细胞（TAM）中MHC-II^hi/PD-1^lo亚群比例和吞噬活性^[7]。在低密度脂蛋白受体敲除（LDLR^−/−）小鼠中，Degarelix（50mg/kg；皮下注射；每2周一次）治疗4个月后，小鼠内脏脂肪积累减少，血糖耐受性改善，主动脉粥样斑块面积和坏死核心面积均显著降低^[8]。