National Clinical Target Validation Laboratory, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
PLoS One. 2011;6(10):e26152. doi: 10.1371/journal.pone.0026152. Epub 2011 Oct 10.
Poly(ADP-ribose) polymerase (PARP) facilitates DNA repair and PARP inhibitors may potentiate the effect of DNA-damaging chemotherapeutic agents in patients with cancer. Collection of peripheral blood mononuclear cells (PBMCs) as a surrogate tissue to monitor PARP inhibitor pharmacodynamic effects has several advantages over tumor biopsy collection, including minimally invasive sample collection and the ability to collect multiple samples for longitudinal assessment of drug effect.
METHODOLOGY/PRINCIPAL FINDINGS: Using our previously validated immunoassay for measuring poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies, we validated a method to quantify PAR levels in PBMCs to monitor the pharmacodynamic effects of the PARP inhibitor ABT-888 in clinical trials. The inter-individual variation in PAR levels was large. No significant difference (P = 0.67) was measured between median baseline PAR levels in 144 healthy volunteers (131.7 pg/1×10(7) PBMCs [interquartile range, 79.5-241.6]) and 49 patients with cancer (149.2 pg/1×10(7) PBMCs [interquartile range, 83.2-249.3]). In addition, PAR levels monitored in healthy volunteers over 3 weeks had considerable intra- and inter-individual variation (range, 44-1073 pg PAR/1×10(7) PBMCs). As a pharmacodynamic model, we quantified changes in PAR levels in human PBMCs treated ex vivo with clinically relevant concentrations of ABT-888. Of 40 healthy volunteer PBMC samples treated with ABT-888, 47.5% had greater than 50% PAR reduction compared to vehicle-treated controls. Considerable inter-sample heterogeneity in PAR levels was measured, and several ABT-888-insensitive samples were identified.
CONCLUSIONS/SIGNIFICANCE: Our results emphasize the importance of using a validated method to measure PAR levels, and support further investigation into the role of PARP in PBMCs. To this end, the PAR immunoassay has been validated for use with PBMCs and incorporated into clinical trials to assess PBMCs as a potential pharmacodynamic surrogate for tumor biopsies in clinical trials of PARP inhibitors.
聚（ADP-核糖）聚合酶（PARP）有助于 DNA 修复，PARP 抑制剂可能增强癌症患者中 DNA 损伤化疗药物的作用。与肿瘤活检采集相比，采集外周血单核细胞（PBMC）作为替代组织来监测 PARP 抑制剂的药效动力学效应具有多个优点，包括微创样本采集和能够采集多个样本以纵向评估药物效果。
方法/主要发现：使用我们之前经过验证的用于测量肿瘤活检中聚（ADP-核糖）（PAR）的免疫测定法，即 PARP 的产物，我们验证了一种方法，以定量 PBMC 中的 PAR 水平来监测 PARP 抑制剂 ABT-888 在临床试验中的药效动力学效应。个体间 PAR 水平的变异较大。在 144 名健康志愿者（131.7 pg/1×10(7) PBMCs [四分位距，79.5-241.6]）和 49 名癌症患者（149.2 pg/1×10(7) PBMCs [四分位距，83.2-249.3]）的中位基线 PAR 水平之间未测量到显著差异（P=0.67）。此外，在健康志愿者中监测的 3 周内的 PAR 水平存在相当大的个体内和个体间差异（范围，44-1073 pg PAR/1×10(7) PBMCs）。作为药效动力学模型，我们定量了在临床上相关浓度的 ABT-888 处理的人 PBMC 中 PAR 水平的变化。在 40 名接受 ABT-888 治疗的健康志愿者 PBMC 样本中，与对照组相比，有 47.5%的样本的 PAR 减少超过 50%。测量到 PAR 水平的样本间存在相当大的异质性，并且确定了几个 ABT-888 不敏感的样本。
结论/意义：我们的结果强调了使用经过验证的方法测量 PAR 水平的重要性，并支持进一步研究 PARP 在 PBMC 中的作用。为此，PAR 免疫测定法已被验证可用于 PBMC，并已纳入临床试验中，以评估 PBMC 作为 PARP 抑制剂临床试验中肿瘤活检的潜在药效动力学替代物。
