PD-0332991 是一种有效的、选择性的细胞周期蛋白依赖性激酶 4/6 抑制剂，在纳摩尔浓度下即可抑制肾细胞癌的增殖，分子标志物可预测其敏感性。

PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity.

机构信息

Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, 924 Westwood Blvd., Suite 1050, Los Angeles, CA 90095, USA.

出版信息

Anticancer Res. 2013 Aug;33(8):2997-3004.

PMID:23898052

Abstract

BACKGROUND

PD-0332991 is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, and was evaluated to determine its anti-proliferative effects in 25 renal cell carcinoma (RCC) cell lines.

MATERIALS AND METHODS

Half-maximal inhibitory concentrations (IC50) of PD-0332991 were determined with cell line proliferation assays, as were its effects on the cell cycle, apoptosis, and retinoblastoma (RB) phosphorylation. Molecular markers for response prediction, including p16, p15, cyclin D1 (CCND1), cyclin E1 (CCNE1), E2F transcription factor 1 (E2F1), RB, CDK4 and CDK6, were studied using array comparative genomic hybridization (CGH) and gene expression.

RESULTS

IC50 values for PD-0332991 ranged from 25.0 nM to 700 nM, and the agent demonstrated G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation. Through genotype and expression data p16, p15 and E2F1 were identified as having significant association between loss and sensitivity to PD-0332991: p16 (p=0.021), p15 (p=0.047), and E2F1 (p=0.041).

CONCLUSION

PD-0332991 has antiproliferative activity in RCC cell lines, and molecular markers predict for sensitivity to this agent.

摘要

背景

PD-0332991 是一种细胞周期蛋白依赖性激酶（CDK）4 和 6 的抑制剂，用于评估其在 25 种肾细胞癌（RCC）细胞系中的抗增殖作用。

材料和方法

用细胞系增殖检测法测定 PD-0332991 的半抑制浓度（IC50），并研究其对细胞周期、细胞凋亡和视网膜母细胞瘤（RB）磷酸化的影响。使用 array 比较基因组杂交（CGH）和基因表达技术研究反应预测的分子标志物，包括 p16、p15、细胞周期蛋白 D1（CCND1）、细胞周期蛋白 E1（CCNE1）、E2F 转录因子 1（E2F1）、RB、CDK4 和 CDK6。

结果

PD-0332991 的 IC50 值范围为 25.0 nM 至 700 nM，该药物表现出 G0/G1 细胞周期停滞、晚期细胞凋亡诱导和 RB 磷酸化阻断。通过基因型和表达数据，p16、p15 和 E2F1 被确定为与 PD-0332991 的缺失和敏感性之间存在显著关联：p16（p=0.021）、p15（p=0.047）和 E2F1（p=0.041）。