Insights into the genetic basis of cancer promise to provide drug developers with new anticancer treatments that are more specific. To design such treatments, new cellular screens are needed to identify drugs that can selectively kill malignant cells containing specific genetic mutations, but not harm other cells. Identification of a drug that is selectively toxic to malignant cells requires testing the drug on equivalent cells that lack the mutant gene, but these cells are not generally available or do not exhibit growth properties comparable to those found in tumors. In this issue (Nature Biotechnology, Vol. 19, No. 10, 01 Oct 2001), Bert Vogelstein and his colleagues describe a drug-screening strategy using cell lines that differ in a single gene (K-Ras) implicated in colon cancer. Their cellular screen allows the identification of drug candidates that specifically target cancerous cells.
To design their screen, the researchers took human cell lines in which the cancer-associated gene K-Ras was either present or absent. These cell lines, which grew at equivalent rates in the absence of inhibitors, were then engineered to produce two different-colored fluorescent proteins - the cell line containing K-ras with a yellow fluorescent protein and the cell line missing K-Ras with a blue fluorescent protein. By tagging each cell line with a different fluorescent protein, the researchers were able to grow the two cell lines together, reducing the number of cells screened and minimizing experimental variation
When the two cell lines together were cocultured together, the effect of different drug inhibitors on the growth of the two cell lines could be monitored by the color of the light emitted. More blue light indicated that the drug inhibited growth of K-Ras cells, whereas more yellow light indicated that the drug inhibited growth K-Ras deleted cells.
In this way, the researchers screened a library of over 29,000 compounds, identifying drug leads that preferentially inhibited the growth of cells carrying the K-Ras gene. When one of these leads was administered to mice implanted with K-Ras-expressing human tumors, tumor growth was inhibited, demonstrating drug potency and validating the strategy. The approach could be modified to allow the identification of therapeutic compounds that target other genes implicated in cancer.
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