Cell-based assays for profiling activity and safety properties of cancer drugs
Cell-based assays for profiling activity and safety properties of cancer drugs
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DOI：
10.1016/j.vascn.2006.02.014
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发表时间：
2006-11-01
影响因子：
1.9
通讯作者：
Post, Joseph M.
中科院分区：
文献类型：
--
作者：
Li, Weiwei;Lam, Marilyn S.;Post, Joseph M.
引言：我们的目标是建立多功能和高容量的检测方法来表征化疗药物的活性和毒性。这些药物的主要抗癌活性指标包括抑制癌细胞增殖和诱导癌细胞凋亡。此外，对正常细胞的细胞毒性和骨髓抑制活性是评价这些药物的毒性的参数。方法：使用一组基于细胞的测定系统，我们研究了选定的癌症药物的活性和毒性特性。评价了药物对多种人类来源的正常细胞和癌细胞类型的影响。结果如下：拓扑异构酶抑制剂（喜树碱，阿霉素和依托泊苷）和微管抑制剂（秋水仙碱和紫杉醇）显示出抗增殖活性，并诱导MDA-231癌细胞凋亡。除阿霉素外，这些药物对正常细胞的毒性相对较低，因为细胞毒性EC 50所需的剂量比癌细胞中抗增殖EC 50的剂量高> 200倍（MDA-231，HL 60）。然而，这些药物是人骨髓祖细胞中骨髓毒性的强效诱导剂。相比之下，DNA烷基化剂（顺铂和卡铂）在MDA-231细胞中是较弱的增殖抑制剂（EC 50> 10 μ M），并且它们的骨髓抑制性也较低。讨论：以市售药物为例，我们的研究建立了一个多检测平台，用于分析抗癌药物的体外性质。在药物发现中，这样的平台将有助于加快早期阶段的先导选择。(c)2006年爱思唯尔公司All rights reserved.
Introduction: Our goal was to establish versatile and high capacity assays to characterize activity and toxicity of chemotherapeutics. The major anti-cancer activity indicators of these agents included inhibition of proliferation and induction of apoptosis to cancer cells. In addition, cytotoxicity and myelosuppressive activity to normal cells were parameters to evaluate toxicity of these drugs. Methods: Using a panel of cell-based assay systems, we investigated activity and toxicity properties of selected cancer drugs. Drug effects on a number of normal and cancer cell types from human origin were evaluated. Results: Topoisomerase inhibitors (camptothecin, doxorubicin and etoposide) and microtubule inhibitors (colchicine and paclitaxel) showed anti-proliferation activity and induced apoptosis in MDA-231 cancer cells. Except for doxorubicin, these drugs had relatively low toxicity to normal cells because the dosage required for cytotoxicity EC50 was > 200-folds higher than the dosage for anti-proliferation EC50 in cancer cells (MDA-231, HL60). However, these drugs were potent inducers of myelotoxicity in human bone marrow progenitor cells. In comparison, the DNA alkylating agents (cisplatin and carboplatin) were less potent proliferation inhibitors (EC50 > 10 mu M) in MDA-231 cells and they were also less myelosuppressive. Discussion: Using marketed drugs as examples, our study established a multiple assay platform for profiling in vitro properties of cancer drugs. In drug discovery, such a platform will help to expedite lead selection at early stage. (c) 2006 Elsevier Inc. All rights reserved.