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© 2005 Oxford University Press
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RNA-based Nanoparticle Treatment Shows Promise in Ewing's Sarcoma Model
If RNA interference is to have any impact on cancer therapy, it will have to pass three tests. It will need to specifically target tumor cells, effectively stop their growth, and do so with few side effects. Now a team of investigators is reporting it has passed all three tests in a mouse model of Ewing's sarcoma, a particularly aggressive cancer that strikes mainly children.
Mark Davis, Ph.D., of the California Institute of Technology, has been working for more than 5 years on a cyclodextrin polymer–based nucleic acid delivery system that can be modified for targeted delivery of siRNA to cancer cells. He has teamed with Timothy Triche, M.D., Ph.D., a pediatric cancer specialist at Children's Hospital in Los Angeles, to target the Ewing's family of tumors, which results when a chromosomal translocation produces a chimeric gene transcript required for tumor growth. Davis, a chemical engineer, has combined an siRNA designed by John Rossi, Ph.D., of the Beckman Research Institute at City of Hope in Duarte, Calif., with his polymer system that has also contains transferrin, a protein that gets taken up by cancer cells, which overexpress the transferrin receptor.
Davis' group reported in April at the annual meeting of the American Association for Cancer Research that long-term treatment with their siRNA nanoparticle formulation inhibited tumor growth in a mouse model of Ewing's sarcoma.
Molecular studies showed that the siRNA nanoparticles reduced levels of the Ewing's transcript by 80% and inhibited growth of a cultured Ewing's tumor cell line. They then administered doses of their experimental construct to mice twice weekly for 4 weeks and measured tumor formation compared with that in control mice. "The treated mice showed little or no tumor growth, while all the others got tumors in multiple places," he said in an interview.
The research team also measured markers of inflammation and looked for evidence of toxicity. "We had no problems with pathology in any of the organs," said Davis. They found no interferon effects, blood chemistry changes, or liver pathology changes, indicating a lack of toxicity.
"We feel fairly confident that this study is a really good example of siRNA being able to do a sequence-specific knockdown of a particular target and having an effect on the disease that is not due to an interferon response or other toxic effects that interfere with trying to interpret your results," he concluded.
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