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¹ Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research; ² Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences; and ³ Laboratory of Biological Chemistry, Department of Applied Biological Chemistry, Faculty of Agricultural and Life Science, University of Tokyo, Tokyo, Japan

Requests for reprints: Takao Yamori, Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan. Phone: 81-3-3520-0111; Fax: 81-3-3570-0484. E-mail: yamori{at}ims.u-tokyo.ac.jp

We have established a panel of 45 human cancer cell lines (JFCR-45) to explore genes that determine the chemosensitivity of these cell lines to anticancer drugs. JFCR-45 comprises cancer cell lines derived from tumors of three different organs: breast, liver, and stomach. The inclusion of cell lines derived from gastric and hepatic cancers is a major point of novelty of this study. We determined the concentration of 53 anticancer drugs that could induce 50% growth inhibition (GI₅₀) in each cell line. Cluster analysis using the GI₅₀s indicated that JFCR-45 could allow classification of the drugs based on their modes of action, which coincides with previous findings in NCI-60 and JFCR-39. We next investigated gene expression in JFCR-45 and developed an integrated database of chemosensitivity and gene expression in this panel of cell lines. We applied a correlation analysis between gene expression profiles and chemosensitivity profiles, which revealed many candidate genes related to the sensitivity of cancer cells to anticancer drugs. To identify genes that directly determine chemosensitivity, we further tested the ability of these candidate genes to alter sensitivity to anticancer drugs after individually overexpressing each gene in human fibrosarcoma HT1080. We observed that transfection of HT1080 cells with the HSPA1A and JUN genes actually enhanced the sensitivity to mitomycin C, suggesting the direct participation of these genes in mitomycin C sensitivity. These results suggest that an integrated bioinformatical approach using chemosensitivity and gene expression profiling is useful for the identification of genes determining chemosensitivity of cancer cells.

Key Words: microarray • chemosensitivity • cancer cell line panel • HSPA1A • bioinformatics

Grant support: Ministry of Education, Culture, Sports, Science and Technology of Japan Aid for Scientific Research on Priority Areas; Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (B) and Exploratory Research; and research grant from the Princess Takamatsu Cancer Research Fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 7/04; revised 12/16/04; accepted 1/25/05.