Improved pharmacodynamic (PD) assessment of low dose PARP inhibitor PD activity for radiotherapy and chemotherapy combination trials
Improved pharmacodynamic (PD) assessment of low dose PARP inhibitor PD activity for radiotherapy and chemotherapy combination trials
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DOI：
10.1016/j.radonc.2017.10.017
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发表时间：
2018-03-01
影响因子：
5.7
通讯作者：
Vens, Conchita
中科院分区：
文献类型：
--
作者：
de Haan, Rosemarie;Pluim, Dick;Vens, Conchita
背景：目前正在评估PARP抑制剂与放疗和/或化疗的联合应用。作为致敏剂，PARP抑制剂在极低浓度下具有活性，因此需要高度灵敏的药效学（PD）测定。目前的临床PD测定部分地不能提供这样的灵敏度。我们的研究的目的是使敏感的PD评价PARP抑制剂的临床sensitivitydevelopment.Material和方法：健康人和奥拉帕尼和放疗治疗的肺癌患者的PBMC收集ELISA为基础的PD-assays.Results：PAR信号放大离体照射后，体外治疗与抑制剂使PARP抑制活性的定量范围扩大。这种“辐射增强PAR”（REP）测定提供了准确的IC 50值，从而也揭示了健康个体之间的差异。在临床放疗联合I期试验中实施，REP-测定显示敏感检测奥拉帕尼治疗患者的PARP抑制，并建立了较强的PARP抑制活性在低日dose.Conclusions：放疗和新型靶向药物的联合试验（S）往往需要不同的和更敏感的PD评估比单药治疗设置。本研究显示了灵敏和适应性PD测定法用于此类组合目的的益处和相关性，并提供了在低每日奥拉帕尼剂量下临床相关细胞PARP抑制活性的证据。(C)2017作者出版社：Elsevier爱尔兰Ltd.
Background: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities. The aim of our study was to enable sensitive PD evaluation of PARP inhibitors for clinical sensitizer development.Material and methods: PBMCs of healthy individuals and of olaparib and radiotherapy treated lung cancer patients were collected for ELISA-based PD-assays.Results: PAR-signal amplification by ex vivo irradiation enabled an extended quantification range for PARP inhibitory activities after ex vivo treatment with inhibitors. This "radiation-enhanced-PAR" (REP) assay provided accurate IC50 values thereby also revealing differences among healthy individuals. Implemented in clinical radiotherapy combination Phase I trials, the REP-assay showed sensitive detection of PARP inhibition in patients treated with olaparib and establishes strong PARP inhibitory activities at low daily doses.Conclusions: Combination trials of radiotherapy and novel targeted agent(s) often require different and more sensitive PD assessments than in the monotherapy setting. This study shows the benefit and relevance of sensitive and adapted PD-assays for such combination purposes and provides proof of clinically relevant cellular PARP inhibitory activities at low daily olaparib doses. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.