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Panel of human cancer cell lines provides valuable database for drug discovery and bioinformatics
1Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, 170-8455, Tokyo, Japan. yamori@ims.u-tokyo.ac.jp
Abstract:
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.
Insights
This study developed a cancer cell line database to predict anticancer drug mechanisms. The system aids in discovering novel drugs like MS-247 and FJ5002, advancing personalized cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Databases of human cancer cell line drug sensitivities offer insights into anticancer drug molecular pharmacology.
- Established a panel of 39 diverse human cancer cell lines and a chemosensitivity database.
Purpose of the Study:
- To establish a cell line panel and database for predicting anticancer drug mechanisms of action.
- To utilize this system for novel anticancer drug discovery and target identification.
- To integrate chemosensitivity and gene expression data for personalized therapy.
Main Methods:
- Profiling anticancer drugs by their differential activity patterns ('fingerprints') against the cell line panel.
- Correlating drug fingerprints with known modes of action.
- Employing the COMPARE algorithm for database mining and DNA microarrays for gene expression profiling.
Main Results:
- A significant correlation was found between drug fingerprints and modes of action.
- Identified MS-247, a novel DNA minor-groove binder with topoisomerase inhibitory and in vivo antitumor activity.
- Discovered FJ5002, a potent novel telomerase inhibitor.
- Identified gene expression profiles linked to chemosensitivity and potential new drug targets.
Conclusions:
- The cell line panel and integrated database are powerful tools for predicting drug mechanisms and discovering novel anticancer agents.
- This approach facilitates drug discovery, target identification, and the development of personalized cancer therapies.