Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy.
Mifepristone prevents repopulation of ovarian cancer cells escaping cisplatin-paclitaxel therapy.
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DOI：
10.1186/1471-2407-12-200
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发表时间：
2012-06-22
期刊：
影响因子：
3.8
通讯作者：
Telleria CM
中科院分区：
文献类型：
--
作者：
Gamarra-Luques CD;Goyeneche AA;Hapon MB;Telleria CM
晚期卵巢癌可通过细胞减灭手术以及铂类和紫杉烷类联合化疗进行治疗。尽管大多数患者对这种策略有急性临床反应，但疾病最终会复发。在这项工作中，我们质疑合成类固醇米非司酮（作为单一疗法抑制卵巢癌细胞的生长）如果在一轮致命的顺铂-紫杉醇联合治疗后给予，是否能够阻止卵巢癌细胞的增殖。我们建立了一种体外方法，其中对顺铂或紫杉醇具有不同敏感性的卵巢癌细胞暴露于一轮致死剂量的顺铂1小时加紫杉醇3小时。此后，将细胞维持在含有或不含米非司酮的培养基中，并评估短期和长期细胞毒性。治疗四天后，顺铂-紫杉醇的致死性表现为细胞数量减少、亚二倍体 DNA 含量增加、细胞凋亡的形态特征、DNA 片段化以及 caspase-3 及其下游底物 PARP 的裂解。米非司酮的短期存在要么增强要么没有改变这种急性致死率。接受顺铂-紫杉醇 7 天后，培养物显示出复发迹象，逃逸的菌落以时间依赖性方式重新填充平板。相反，暴露于顺铂-紫杉醇，然后暴露于米非司酮的培养物不仅没有在初始化疗后显示出再增殖的迹象，而且与顺铂-紫杉醇后再增殖的细胞相比，它们的克隆形成能力也大大降低。联合使用致死剂量的顺铂和紫杉醇后，米非司酮的细胞抑制浓度会阻止存活并逃离细胞毒性药物的残余细胞的重新增殖。
Advanced ovarian cancer is treated with cytoreductive surgery and combination platinum- and taxane-based chemotherapy. Although most patients have acute clinical response to this strategy, the disease ultimately recurs. In this work we questioned whether the synthetic steroid mifepristone, which as monotherapy inhibits the growth of ovarian cancer cells, is capable of preventing repopulation of ovarian cancer cells if given after a round of lethal cisplatin-paclitaxel combination treatment. We established an in vitro approach wherein ovarian cancer cells with various sensitivities to cisplatin or paclitaxel were exposed to a round of lethal doses of cisplatin for 1 h plus paclitaxel for 3 h. Thereafter, cells were maintained in media with or without mifepristone, and short- and long-term cytotoxicity was assessed. Four days after treatment the lethality of cisplatin-paclitaxel was evidenced by reduced number of cells, increased hypodiploid DNA content, morphological features of apoptosis, DNA fragmentation, and cleavage of caspase-3, and of its downstream substrate PARP. Short-term presence of mifepristone either enhanced or did not modify such acute lethality. Seven days after receiving cisplatin-paclitaxel, cultures showed signs of relapse with escaping colonies that repopulated the plate in a time-dependent manner. Conversely, cultures exposed to cisplatin-paclitaxel followed by mifepristone not only did not display signs of repopulation following initial chemotherapy, but they also had their clonogenic capacity drastically reduced when compared to cells repopulating after cisplatin-paclitaxel. Cytostatic concentrations of mifepristone after exposure to lethal doses of cisplatin and paclitaxel in combination blocks repopulation of remnant cells surviving and escaping the cytotoxic drugs.
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影响因子：
8
作者：
Cooke, S. L.;Ng, C. K. Y.;Melnyk, N.;Garcia, M. J.;Hardcastle, T.;Temple, J.;Langdon, S.;Huntsman, D.;Brenton, J. D.
通讯作者：
Brenton, J. D.
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.9
作者：
Erenpreisa, Jekaterina;Salmina, Kristine;Anisimov, Alim P.
通讯作者：
Anisimov, Alim P.
影响因子：
3.9
作者：
Erenpreisa, Jekaterina;Cragg, Mark S.
通讯作者：
Cragg, Mark S.
影响因子：
4.8
作者：
Hayakawa, J;Ohmichi, M;Murata, Y
通讯作者：
Murata, Y