The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines
The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines
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DOI：
10.1007/s10637-010-9467-6
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发表时间：
2011-12-01
影响因子：
3.4
通讯作者：
John, Veena
中科院分区：
文献类型：
--
作者：
Budman, Daniel R.;Tai, Julia;John, Veena
尽管铂类药物治疗改善了转移性卵巢癌患者的短期生存率，但大多数患者仍会复发并最终死于疾病。目前，大量的药物正在开发中，但如何将它们联合收割机以提高疗效仍然主要是经验性的。我们已经使用了确定的细胞系的短期体外培养，应用有希望的试剂，并使用MTT测定法分析细胞死亡，以鉴定潜在有用的组合。使用中值效应分析、曲线移动分析和凋亡测定，我们可以确定当药物一起应用时是协同的还是拮抗的。最多可以联合研究三种药物。使用三种细胞系：SK-OV-3、CaOV-3和ES-2（透明细胞肿瘤），我们已经鉴定了帕比司他（LBH-589），一种在临床试验中广泛的组蛋白脱乙酰酶抑制剂，显示出与吉西他滨、与紫杉醇的总体协同作用，以及与5 ′ DFUR的协同作用的累加。帕比司他、多柔比星和卡铂的三联体在这些细胞系中尤其具有协同作用。这些效应是细胞毒性的，而不是细胞抑制性的。由于所有这些药物都在临床上使用，我们已经确定了需要进一步研究的组合。
Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5'DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.