Researchers have developed a new strategy to identify potential anticancer compounds. The system makes it possible to screen for compounds that can selectively kill cells that carry specific mutations often found in cancer cells, such as those in cell cycle checkpoint proteins. The findings appear in the Jan. 16 issue of the Journal of the National Cancer Institute.

Current approaches to anticancer drug discovery are target-based, where researchers design compounds that specifically interact with proteins that are involved in cancer. Although this approach has led to the discovery of compounds such as angiogenesis inhibitors, it is limited by the lack of knowledge about the specificity of the compounds, say Heather M. Dunstan, Ph.D., John R. Lamb, Ph.D., and colleagues at the Fred Hutchinson Cancer Research Center, Seattle.

The new cell-based approach, rather, is based on screening compounds against cells with specific genetic mutations. Using this approach, researchers can screen an entire library of compounds against many cells that each contain a different genetic mutation. Compounds that are specifically toxic against cells with defined mutations would undergo further testing.

The approach is adaptable to the so-called high-throughput screening method, which allows researchers to screen large libraries of compounds and quickly identify lead compounds, says Frank M. Balis, M.D., National Cancer Institute, in an editorial.

Using their three-stage, cell-based approach, the authors identified 39 new compounds selective for yeast cells that have a faulty DNA repair enzyme called rad50. The authors found these compounds by screening more than 85,000 compounds from the National Cancer Institute’s repository for compounds that are selective against yeast cells with defective DNA repair enzymes.

Although exactly how the compounds act is yet to be determined, the authors maintain that “it is better to have compounds with a known selectivity but an unknown target than to have compounds with a known target and an unknown specificity.”

In his editorial, Balis says that target-based screening and target-specific cell-based screening, such as the approach reported by Dunstan and her colleagues, are complementary tools that can be used to identify additional selective anticancer drugs. “They represent a dramatic shift in the drug discovery process that is likely to have an impact not only on the pharmacologic properties of new anticancer agents reaching the clinic but also on our approach to clinical drug development and the treatment of cancer,” says Balis.

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Contacts: Susan Edmonds, Fred Hutchinson Cancer Research Center, (206) 667-2896, fax: (206) 667-7005, sedmonds@fhcrc.org; editorial: NCI Press Office, (301) 496-6641

Dunstan HM, Ludlow C, Goehle S, Cronk M, Szankasi P, Evans DR, et al. Cell-based assays for identification of novel double-strand break-inducing agents. J Natl Cancer Inst 2002;94:88–94.

Editorial: Balis FM. Evolution of anticancer drug discovery and the role of cell-based screening. J Natl Cancer Inst 2002;94:78–9.

Attribution to the Journal of the National Cancer Institute is requested in all news coverage.

Contact: Linda Wang, jncinews@oup-usa.org, 301-594-2927, Journal of the National Cancer Institute

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