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1
Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer.雄激素受体失活有助于17α-羟化酶/17,20-裂解酶抑制剂3β-羟基-17-(1H-苯并咪唑-1-基)雄甾-5,16-二烯在前列腺癌中的抗肿瘤疗效。
Mol Cancer Ther. 2008 Aug;7(8):2348-57. doi: 10.1158/1535-7163.MCT-08-0230.
2
Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model.新型C-17-杂芳基甾体CYP17抑制剂/抗雄激素：合成、体外生物学活性、药代动力学及在LAPC4人前列腺癌异种移植模型中的抗肿瘤活性
J Med Chem. 2005 Apr 21;48(8):2972-84. doi: 10.1021/jm040202w.
3
Discovery and development of Galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer.用于治疗各阶段前列腺癌的加列酮（TOK-001或VN/124-1）的发现与研发。
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Effects of new 17alpha-hydroxylase/C(17,20)-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo.新型17α-羟化酶/C（17,20）-裂解酶抑制剂对LNCaP前列腺癌细胞体外和体内生长的影响
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6
Potent CYP17 inhibitors: improved syntheses, pharmacokinetics and anti-tumor activity in the LNCaP human prostate cancer model.强效CYP17抑制剂：在LNCaP人前列腺癌模型中的合成改进、药代动力学及抗肿瘤活性
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17alpha-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response.17α-羟化酶/17,20裂解酶抑制剂VN/124-1通过诱导内质网应激反应抑制雄激素非依赖性前列腺癌细胞的生长。
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Molecular Mechanisms of Noncoding RNA in the Occurrence of Castration-Resistant Prostate Cancer.非编码 RNA 在去势抵抗性前列腺癌发生中的分子机制。
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Galeterone for the treatment of advanced prostate cancer: the evidence to date.醋酸阿比特龙用于治疗晚期前列腺癌：迄今的证据
Drug Des Devel Ther. 2016 Jul 15;10:2289-97. doi: 10.2147/DDDT.S93941. eCollection 2016.

本文引用的文献

1
Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer.睾酮抑制后前列腺内雄激素及雄激素调节的基因表达持续存在：对去势抵抗性前列腺癌的治疗意义
Cancer Res. 2007 May 15;67(10):5033-41. doi: 10.1158/0008-5472.CAN-06-3332.
2
A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells.雄激素受体在雄激素敏感和不敏感前列腺癌细胞中的促进作用。
Nucleic Acids Res. 2007;35(8):2767-76. doi: 10.1093/nar/gkm198. Epub 2007 Apr 10.
3
Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer.肾上腺雄激素的胞内代谢在雄激素依赖性前列腺癌中的重要性。
Prostate Cancer Prostatic Dis. 2007;10(3):301-6. doi: 10.1038/sj.pcan.4500956. Epub 2007 Mar 27.
4
Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells.3,3'-二吲哚甲烷对雄激素受体的下调作用有助于抑制激素敏感的LNCaP和不敏感的C4-2B前列腺癌细胞的增殖并诱导其凋亡。
Cancer Res. 2006 Oct 15;66(20):10064-72. doi: 10.1158/0008-5472.CAN-06-2011.
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Regulation of androgen receptor activity by tyrosine phosphorylation.酪氨酸磷酸化对雄激素受体活性的调节。
Cancer Cell. 2006 Oct;10(4):309-19. doi: 10.1016/j.ccr.2006.08.021.
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Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22 prostate cancer cells.雄激素受体对雄激素非依赖性CWR22前列腺癌细胞的细胞周期进程仍然至关重要。
Am J Pathol. 2006 Aug;169(2):682-96. doi: 10.2353/ajpath.2006.051047.
7
Degradation and beyond: control of androgen receptor activity by the proteasome system.降解及其他：蛋白酶体系统对雄激素受体活性的调控
Cell Mol Biol Lett. 2006;11(1):109-31. doi: 10.2478/s11658-006-0011-9.
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Cancer statistics, 2006.2006年癌症统计数据。
CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30. doi: 10.3322/canjclin.56.2.106.
9
Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.雄激素非依赖性前列腺癌中负责将肾上腺雄激素转化为睾酮的基因表达增加。
Cancer Res. 2006 Mar 1;66(5):2815-25. doi: 10.1158/0008-5472.CAN-05-4000.
10
CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets.细胞色素P450 17α-羟化酶和11β-羟化酶作为药物开发靶点
Pharmacol Ther. 2006 Jul;111(1):27-52. doi: 10.1016/j.pharmthera.2005.07.006. Epub 2006 Jan 19.

雄激素受体失活有助于17α-羟化酶/17,20-裂解酶抑制剂3β-羟基-17-(1H-苯并咪唑-1-基)雄甾-5,16-二烯在前列腺癌中的抗肿瘤疗效。

Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer.

作者信息

Vasaitis Tadas, Belosay Aashvini, Schayowitz Adam, Khandelwal Aakanksha, Chopra Pankaj, Gediya Lalji K, Guo Zhiyong, Fang Hong-Bin, Njar Vincent C O, Brodie Angela M H

机构信息

Health Sciences Facility, University of Maryland, 685 West Baltimore Street, Baltimore, MD 21201, USA.

出版信息

Mol Cancer Ther. 2008 Aug;7(8):2348-57. doi: 10.1158/1535-7163.MCT-08-0230.

DOI:10.1158/1535-7163.MCT-08-0230
PMID:18723482
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2643345/
Abstract

We previously reported that our novel compound 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17alpha-hydroxylase/17,20-lyase (CYP17) inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel CYP17 inhibitors also cause down-regulation of androgen receptor (AR) protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, Casodex, and show that VN/124-1 is more potent than castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 versus 2410.28 mm(3) in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with Casodex (0.13 mmol/kg twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with Casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/124-1 is more efficacious than castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of prostate cancer.

摘要

我们之前报道过，我们的新型化合物3β-羟基-17-(1H-苯并咪唑-1-基)雄甾-5,16-二烯(VN/124-1)是一种强效的17α-羟化酶/17,20-裂解酶(CYP17)抑制剂/抗雄激素，能强烈抑制严重联合免疫缺陷小鼠体内人前列腺癌LAPC4肿瘤异种移植物的形成和增殖。在本研究中，我们报道VN/124-1和其他新型CYP17抑制剂在体外和体内也会导致雄激素受体(AR)蛋白表达下调。这种作用机制似乎有助于它们的抗肿瘤功效。我们比较了VN/124-1与去势及一种临床使用的抗雄激素药物比卡鲁胺的体内抗肿瘤功效，结果显示在LAPC4异种移植模型中，VN/124-1比去势更有效。用VN/124-1(0.13 mmol/kg，每日两次)治疗也能非常有效地预防LAPC4肿瘤的形成(对照组为2410.28 mm³，治疗组为6.94 mm³)。VN/124-1(0.13 mmol/kg，每日两次)以及VN/124-1(0.13 mmol/kg，每日两次)+去势分别使LAPC4肿瘤异种移植物消退了26.55%和60.67%。与对照组相比，用比卡鲁胺(0.13 mmol/kg，每日两次)或去势治疗均导致显著的肿瘤抑制。此外，与比卡鲁胺或去势治疗导致AR蛋白表达显著上调相反，用VN/124-1治疗导致AR蛋白表达显著下调。结果表明，VN/124-1通过多种机制发挥作用(CYP17抑制、竞争性抑制以及AR下调)。这些作用有助于抑制LAPC4肿瘤的形成，并使已形成肿瘤的生长消退。在LAPC4异种移植模型中，VN/124-1比去势更有效，这表明该化合物具有治疗前列腺癌的潜力。