New Assay Helps Identify Anticancer Agents

NEW YORK (Reuters Health) Jan 15 – Researchers have developed a cell-based assay that is capable of identifying molecules that are selectively toxic to cells with defined mutations, according to a report published in the January 16th issue of the Journal of the National Cancer Institute.

The assay, developed by Dr. John R. Lamb and colleagues, at the Fred Hutchinson Cancer Research Center in Seattle, was tested in a three-stage strategy in which potential anticancer agents were tested against matched pairs of yeast cell lines. One line contained a defined genetic alteration, while the other contained the corresponding wild-type gene.

Using this method, the researchers can determine an agent's selective toxicity, but not its exact molecular target. However, the authors believe it is more useful to know an agent's selectivity and not its specificity than the converse.

The investigators tested their assay on more than 85,000 compounds in the National Cancer Institute compound registry. Specifically, they were looking for agents that were selectively toxic to double-strand break-repair defective cells.

The assay yielded 126 compounds that were selectively toxic. Of these, the researchers identified two novel topoisomerase II agents that were equipotent to etoposide. In addition, five compounds with topoisomerase I-dependent toxicity and one compound, which bound directly to DNA and induced strand breaks, were identified.

The authors believe that cell-based assays could ultimately be used to identify agents that are selectively toxic to cells with cell cycle gene mutations. There are currently no selectively toxic agents for these types of cells, they point out.

In a related editorial, Dr. Frank M. Balis, from the National Cancer Institute in Bethesda, Maryland, comments that "unlike target-based assays, this cell-based assay is not a mechanistic screen." However, "determining the mechanism of action of selectively toxic agents from this screen may identify new molecular targets…for subsequent target-based screening."

J Natl Cancer Inst 2002;94:78-79, 88-94.

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