基于机制的药物组合与 DNA 链断裂核苷类似物 CNDAC,Molecular Cancer Therapeutics

当前位置： X-MOL 学术 › Mol. Cancer Ther. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

基于机制的药物组合与 DNA 链断裂核苷类似物 CNDAC
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2016-07-29 , DOI: 10.1158/1535-7163.mct-15-0801
Xiaojun Liu ₁ , Yingjun Jiang ₁ , Billie Nowak ₁ , Sarah Hargis ₁ , William Plunkett _{1,

2}

Affiliation

CNDAC（2'-C-cyano-2'-deoxy-1-β-d-arabino-pentofuranosyl-cytosine，DFP10917）及其口服生物可利用的前药sapacitabine正在进行血液系统恶性肿瘤和实体瘤的临床试验。诱导 DNA 链断裂的独特作用机制将 CNDAC 与其他脱氧胞苷类似物区分开来。为了优化 CNDAC 的临床潜力，我们探索了多种策略，将 CNDAC 与针对目前临床使用的不同 DNA 损伤修复途径的化疗药物相结合。在某些 DNA 修复蛋白精通和缺陷的成对细胞系中，确定了通过克隆形成试验确定的每种药剂降低增殖潜力的能力。随后，每种药剂以固定的浓度比例与 CNDAC 联合使用。通过中值效应分析定量克隆形成，并计算组合指数。c-Abl 激酶抑制剂伊马替尼在 HCT116 细胞中与 CNDAC 具有协同作用，无论 p53 状态如何。干扰同源重组 (HR) 修复或碱基切除修复 (BER) 的 PARP1 抑制剂和导致通过 BER 途径修复的 DNA 损伤的药物如替莫唑胺也与 CNDAC 协同作用。氮芥类苯达莫司汀和胞嘧啶或铂化合物的毒性与 CNDAC 相加，它们产生通过核苷酸切除修复和 HR 修复的 DNA 加合物。CNDAC 与紫杉烷有丝分裂抑制剂（紫杉醇和多西紫杉醇）的组合也实现了附加的细胞杀伤。在允许大多数野生型细胞存活的浓度下，协同或相加组合效应在 HR 缺陷细胞中具有选择性。这项研究为 CNDAC 与其他活性药物的结合提供了机械原理。摩尔癌症治疗; 15(10); 2302-13。©2016 AACR。

"点击查看英文标题和摘要"

Mechanism-Based Drug Combinations with the DNA Strand-Breaking Nucleoside Analog CNDAC

CNDAC (2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosyl-cytosine, DFP10917) and its orally bioavailable prodrug, sapacitabine, are undergoing clinical trials for hematologic malignancies and solid tumors. The unique action mechanism of inducing DNA strand breaks distinguishes CNDAC from other deoxycytidine analogs. To optimize the clinical potentials of CNDAC, we explored multiple strategies combining CNDAC with chemotherapeutic agents targeting distinct DNA damage repair pathways that are currently in clinical use. The ability of each agent to decrease proliferative potential, determined by clonogenic assays, was determined in paired cell lines proficient and deficient in certain DNA repair proteins. Subsequently, each agent was used in combination with CNDAC at fixed concentration ratios. The clonogenicity was quantitated by median effect analysis, and a combination index was calculated. The c-Abl kinase inhibitor imatinib had synergy with CNDAC in HCT116 cells, regardless of p53 status. Inhibitors of PARP1 that interfere with homologous recombination (HR) repair or base excision repair (BER) and agents such as temozolomide that cause DNA damage repaired by the BER pathway were also synergistic with CNDAC. The toxicity of the nitrogen mustards bendamustine and cytoxan, or of platinum compounds, which generate DNA adducts repaired by nucleotide excision repair and HR, was additive with CNDAC. An additive cell killing was also achieved by the combination of CNDAC with taxane mitotic inhibitors (paclitaxel and docetaxel). At concentrations that allow survival of the majority of wild-type cells, the synergistic or additive combination effects were selective in HR-deficient cells. This study provides mechanistic rationales for combining CNDAC with other active drugs. Mol Cancer Ther; 15(10); 2302–13. ©2016 AACR.

更新日期：2016-07-29

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南