Yamori Takao
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, 170-8455, Tokyo, Japan.
Cancer Chemother Pharmacol. 2003 Jul;52 Suppl 1:S74-9. doi: 10.1007/s00280-003-0649-1. Epub 2003 Jun 18.
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-247, 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 chemosensitivities and gene expression profiles of the cell-line panel, could provide a basis for drug discovery and personalized therapy.
美国国立癌症研究所（NCI）以及我们实验室所开展的研究表明，包含多种人类癌细胞系药物敏感性的数据库能提供有关抗癌药物分子药理学的宝贵信息。我们建立了一个由39种不同人类癌症细胞系组成的细胞库，并开发了它们的化学敏感性数据库。根据药物对细胞系的“指纹图谱”，即差异活性模式，对药物进行了分析。正如在NCI的60种细胞系组成的细胞库中所观察到的那样，一种药物的指纹图谱与其作用模式之间存在显著相关性。因此，我们的细胞系库是预测新化合物作用模式的有力工具。我们一直在将这个系统用于药物发现，并结合各种基于靶点的药物筛选。我们利用该系统鉴定出一种新型DNA小沟结合剂MS - 247，它对拓扑异构酶I和II具有抑制活性，并且对多种人类癌症异种移植瘤具有强大的体内抗肿瘤活性。我们还通过使用COMPARE算法挖掘我们的数据库，随后进行实验验证，发现了一种强效的新型端粒酶抑制剂FJ5002。我们通过使用DNA微阵列研究细胞系的基因表达谱，以找到决定细胞化学敏感性的谱图以及抗癌药物的新靶点。我们的综合数据库，包括细胞系库的化学敏感性和基因表达谱，可为药物发现和个性化治疗提供依据。
