Panel of human cancer cell lines provides valuable database for drug discovery and bioinformatics
Panel of human cancer cell lines provides valuable database for drug discovery and bioinformatics
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DOI：
10.1007/s00280-003-0649-1
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发表时间：
2003-07-01
影响因子：
3
通讯作者：
Yamori, T
中科院分区：
文献类型：
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作者：
Yamori, T
在美国国家癌症研究所 (NCI) 和我们实验室进行的研究表明，包括许多人类癌细胞系组的药物敏感性在内的数据库提供了有关抗癌药物分子药理学的宝贵信息。我们建立了一组 39 种不同人类癌症细胞系，并开发了它们的化学敏感性数据库。药物根据其“指纹”（针对细胞系的差异活性模式）进行分析。正如在 NCI 60 个细胞系小组中观察到的那样，药物指纹与其作用模式之间存在显着相关性。因此，我们的细胞系面板是预测新化合物作用模式的强大工具。我们一直在使用该系统进行药物发现，并结合各种基于目标的药物筛选。我们使用该系统鉴定了一种新型 DNA 小沟结合物 MS-2471，它对拓扑异构酶 I 和 II 具有抑制活性，并对各种人类癌症异种移植物具有有效的体内抗肿瘤活性。通过使用 COMPARE 算法挖掘我们的数据库，然后进行实验验证，我们还发现了一种有效的新型端粒酶抑制剂 FJ5002。我们通过使用 DNA 微阵列研究了细胞系的基因表达谱，以找到决定细胞化学敏感性和抗癌药物新靶标的谱。我们的综合数据库，包括细胞系组的化疗敏感性和基因表达谱，可以为药物发现和个性化治疗提供基础。
Studies conducted at the US National Cancer Institute (NCI) and in our laboratory show that databases including the drug sensitivities of panels of many human cancer cell lines provide valuable information on the molecular pharmacology of anticancer drugs. We established a panel of 39 cell lines of various human cancers and developed a database of their chemosensitivities. Drugs were profiled in terms of their "fingerprints", patterns of differential activity against the cell lines. There was a significant correlation between a drug's fingerprint and its mode of action, as observed in the NCI panel of 60 cell lines. Therefore our cell-line panel is a powerful tool to predict the modes of action of new compounds. We have been using this system for drug discovery, coupled with various target-based drug screenings. We used the system to identify a novel DNA minor-groove binder, MS-2471 which has inhibitory activity against topoisomerases I and II, and potent in vivo antitumor activity against various human cancer xenografts. We also discovered a potent novel telomerase inhibitor, FJ5002, by mining our database with the COMPARE algorithm, followed by experimental validation. We investigated the gene expression profiles of the cell lines by using DNA microarrays to find profiles determining cellular chemosensitivity and new targets for anticancer drugs. Our integrated database, including the chemo sensitivities and gene expression profiles of the cell-line panel, could provide a basis for drug discovery and personalized therapy.