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DNA-damage test could aid drug development

om an established cell-culture system based on mouse fetal liver cells to create a new system based on adult red cell precursors from mouse bone marrow. Shuga patiently optimized the system, which allows the precursor cells to proliferate and differentiate in the normal way, dividing four or five times before losing their nucleus and becoming immature red blood cells.

Shuga then studied the way these developing cells reacted to three toxic DNA- damaging agents whose effects had been studied by Samson's lab, and found the results correlated well with results from the existing test. Additionally, he experimented with mutant mice created by Samson's lab that are deficient in certain DNA-repair systems. The bone marrow cells derived from these mice, and the cells cultured from that bone marrow, proved more sensitive to the toxic agents than were the cultured cells from normal mice, further confirming the results.

With the new assay, "instead of testing one chemical and one dose in one animal, you'll be able to take one animal, get the bone marrow out and test a thousand different conditions," Samson says. "You'll be able to look in more detail at different doses given at different times in the cell differentiation process."

"This is a much cheaper assay that's at least as predictive as previous assays," emphasizes Griffith, "and drug developers can afford to use it a lot earlier in the drug development process." It also could help to avoid issues with animal testing. "The European Union is trying to minimize animal testing," Shuga points out. "A ban on animal testing of cosmetic products goes into effect in 2009."

Next steps in the research, which may be carried out by industry partners, will be to test the assay in rats and other organisms, and with a wide variety of other toxic chemicals.

"This research is the first stage in a new type of clinical drug toxicity test," says Lodish. "And although we haven't done it, you
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Source:Whitehead Institute for Biomedical Research


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