Effects of new 17alpha-hydroxylase/C(17,20)-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo.
Effects of new 17alpha-hydroxylase/C(17,20)-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo.
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新的17Alpha-羟化酶/C（17,20） - 溶剂抑制剂对体外和体内LNCAP前列腺癌细胞生长的影响。
DOI：
10.1038/sj.bjc.6690739
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发表时间：
1999-10
影响因子：
8.8
通讯作者：
Brodie, AMH
中科院分区：
文献类型：
--
作者：
Grigoryev, DN;Long, BJ;Nnane, IP;Njar, VCO;Liu, Y;Brodie, AMH
关键词：
我们的实验室一直在开发睾丸和肾上腺雄激素合成的关键调节酶17α-羟化酶/C17，20-裂解酶（P450 c17）的新抑制剂，旨在改善前列腺癌的治疗。我们设计并评价了两组唑基甾体化合物：Δ5-非竞争性抑制剂（Δ 5 NCIs），VN/63-1，VN/85-1，VN/87-1及其相应的Δ4衍生物（Δ 4 NCIs），VN/107-1，VN/108-1和VN/109-1。将人P450 c17基因转染到LNCaP人前列腺癌细胞中，并利用所得LNCaP-CYP 17细胞来评估新唑基类固醇的抑制效力。VN/85-1和VN/108-1的IC 50值最低，分别为1.25 ± 0.44 nM和2.96 ± 0.78 nM，远低于已知的P450抑制剂酮康唑（80.7 ± 1.8 nM）。为了确定化合物是否对野生型LNCaP细胞的增殖具有直接作用，进行细胞生长研究。所有的Δ 5 NCI和VN/108-1阻断雄激素的促生长作用。在无类固醇培养基中，Δ 5 NCI使LNCaP细胞的增殖降低35- 40%，而所有Δ 4 NCI刺激LNCaP细胞生长1.5- 2倍。在雄激素受体（AR）结合研究中，为确定该效应的机制，所有Δ 4 NCI（5 μM）从LNCaP AR中置换了77-82%的合成雄激素R1881（5 nM）。抗雄激素氟替卡松和Δ 5 NCIs分别取代53%和32-51%的与AR结合的R1881。这些结果表明，Δ 5 NCI也可以作为抗雄激素。我们在携带LNCaP肿瘤异种移植物的雄性严重联合免疫缺陷小鼠中进一步评估了我们的抑制剂。在该模型中，VN/85-1在抑制肿瘤生长方面与非那肽一样有效（分别为26%和28%抑制），VN/87-1的抑制作用与去势的抑制作用相似（分别为33%和36%抑制）。这些结果表明VN/85-1和VN/87-1可能是治疗前列腺癌的潜在候选者。© 1999癌症研究运动
Our laboratory has been developing new inhibitors of a key regulatory enzyme of testicular and adrenal androgen synthesis 17α-hydroxylase/C17,20-lyase (P450c17), with the aim of improving prostate cancer treatment. We designed and evaluated two groups of azolyl steroids: Δ5-non-competitive inhibitors (Δ5NCIs), VN/63-1, VN/85-1, VN/87-1 and their corresponding Δ4 derivatives (Δ4NCIs), VN/107-1, VN/108-1 and VN/109-1. The human P450c17 gene was transfected into LNCaP human prostate cancer cells, and the resultant LNCaP-CYP17 cells were utilized to evaluate the inhibitory potency of the new azolyl steroids. VN/85-1 and VN/108-1 had the lowest IC50 values of 1.25 ± 0.44 nM and 2.96 ± 0.78 nM respectively, which are much lower than that of the known P450 inhibitor ketoconazole (80.7 ± 1.8 nM). To determine whether the compounds had direct actions on proliferation of wild-type LNCaP cells, cell growth studies were performed. All of the Δ5NCIs and VN/108-1 blocked the growth-stimulating effects of androgens. In steroid-free media, the Δ5NCIs decreased the proliferation of LNCaP cells by 35–40%, while all of the Δ4NCIs stimulated LNCaP cells growth 1.5- to 2-fold. In androgen receptor (AR) binding studies, carried out to determine the mechanism of this effect, all of the Δ4NCIs (5 μM) displaced 77–82% of synthetic androgen R1881 (5 nM) from the LNCaP AR. The anti-androgen flutamide and the Δ5NCIs displaced 53% and 32–51% of R1881 bound to AR respectively. These results suggested that the Δ5NCIs may also be acting as anti-androgens. We further evaluated our inhibitors in male severe combined immuno- deficient mice bearing LNCaP tumour xenografts. In this model VN/85-1 was as effective as finasteride at inhibiting tumor growth (26% and 28% inhibition, respectively) and the inhibitory effect of VN/87-1 was similar to that of castration (33% and 36% inhibition respectively). These results suggest that VN/85-1 and VN/87-1 may be potential candidates for treatment of prostate cancer. © 1999 Cancer Research Campaign
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DOI：
10.1016/s0006-291x(05)80067-1
发表时间：
1990-12-14
影响因子：
3.1
作者：
VELDSCHOLTE, J;RISSTALPERS, C;MULDER, E
通讯作者：
MULDER, E
影响因子：
30.8
作者：
VISAKORPI, T;HYYTINEN, E;KALLIONIEMI, OP
通讯作者：
KALLIONIEMI, OP
DOI：
10.1111/j.1464-410x.1986.tb05426.x
发表时间：
1986-02-01
期刊：
BRITISH JOURNAL OF UROLOGY
影响因子：
--
作者：
WILLIAMS, G;KERLE, DJ;BLOOM, SR
通讯作者：
BLOOM, SR
影响因子：
4.8
作者：
WONG, CI;KELCE, WR;WILSON, EM
通讯作者：
WILSON, EM
影响因子：
158.5
作者：
CRAWFORD, ED;EISENBERGER, MA;GOODMAN, PJ
通讯作者：
GOODMAN, PJ