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Evaluation of Action Mechanisms of Toxic Chemicals Using JFCR39, a Panel of Human Cancer Cell Lines

Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan (N.N., T.N., K.Y., T.Y.); Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan (N.N., J.K.); and Second Department of Surgery, Tokai University School of Medicine, Boseidai, Isehara-City, Kanagawa, Japan (T.N., S.S., H.M.)

We previously established a panel of human cancer cell lines, JFCR39, coupled to an anticancer drug activity database; this panel is comparable with the NCI60 panel developed by the National Cancer Institute. The JFCR39 system can be used to predict the molecular targets or evaluate the action mechanisms of the test compounds by comparing their cell growth inhibition profiles (i.e., fingerprints) with those of the standard anticancer drugs using the COMPARE program. In this study, we used this drug activity database-coupled JFCR39 system to evaluate the action mechanisms of various chemical compounds, including toxic chemicals, agricultural chemicals, drugs, and synthetic intermediates. Fingerprints of 130 chemicals were determined and stored in the database. Sixty-nine of 130 chemicals (60%) satisfied our criteria for the further analysis and were classified by cluster analysis of the fingerprints of these chemicals and several standard anticancer drugs into the following three clusters: 1) anticancer drugs, 2) chemicals that shared similar action mechanisms (for example, ouabain and digoxin), and 3) chemicals whose action mechanisms were unknown. These results suggested that chemicals belonging to a cluster (i.e., a cluster of toxic chemicals, a cluster of anticancer drugs, etc.) shared similar action mechanism. In summary, the JFCR39 system can classify chemicals based on their fingerprints, even when their action mechanisms are unknown, and it is highly probable that the chemicals within a cluster share common action mechanisms.

Address correspondence to: Takao Yamori, Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan. E-mail: yamori{at}jfcr.or.jp, 07a$sl