Li Weiwei, Lam Marilyn S, Birkeland Andrew, Riffel Angela, Montana Leticia, Sullivan Mark E, Post Joseph M
Department of Pharmacology, Berlex Biosciences, Richmond, CA 94804, USA.
J Pharmacol Toxicol Methods. 2006 Nov-Dec;54(3):313-9. doi: 10.1016/j.vascn.2006.02.014. Epub 2006 Mar 27.
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.
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.
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 EC(50) was >200-folds higher than the dosage for anti-proliferation EC(50) 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 (EC(50)>10 microM) in MDA-231 cells and they were also less myelosuppressive.
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.
我们的目标是建立通用且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对癌细胞增殖的抑制和凋亡的诱导。此外，对正常细胞的细胞毒性和骨髓抑制活性是评估这些药物毒性的参数。
使用一组基于细胞的检测系统，我们研究了所选抗癌药物的活性和毒性特性。评估了药物对多种源自人类的正常和癌细胞类型的作用。
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）在MDA - 231癌细胞中显示出抗增殖活性并诱导凋亡。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（MDA - 231、HL60）中抗增殖EC(50)所需的剂量高200倍以上。然而，这些药物是人类骨髓祖细胞中骨髓毒性的强效诱导剂。相比之下，DNA烷化剂（顺铂和卡铂）在MDA - 231细胞中作为增殖抑制剂的效力较低（EC(50)>10 microM），并且它们的骨髓抑制作用也较小。
以市售药物为例，我们的研究建立了一个用于分析抗癌药物体外特性的多重检测平台。在药物研发中，这样的平台将有助于在早期加速先导化合物的筛选。
