The researchers plucked a critical "death domain" from a key molecule in the self-destruction mechanism of a cell, stiffened its Slinky-like structure with chemical "staples," and used it as a highly specific weapon to destroy leukemia cells. The findings will be published in the Sept. 3 issue of the journal Science.
"We have demonstrated an approach for getting at potential new drugs by using natural sequences [of amino acids] that have known biological effects," says Stanley J. Korsmeyer, MD, of Dana-Farber, co-senior author of the paper. "In this case we took the critical killer domain out of a pro-death molecule and chemically reinforced it, so we were able to get it into cancer cells and kill them."
Loren D. Walensky, MD, PhD, of Dana-Farber and Children's Hospital Boston is the paper's first author and Gregory L. Verdine, PhD, of Harvard University, is co- senior author.
Korsmeyer and his colleagues have pioneered studies of apoptosis, or programmed cell death, that rids the body of damaged or unneeded cells. Apoptosis is directed by a complex collection of proteins in a yin-yang-like balance and is activated by a variety of external and internal signals. Some of the proteins set in motion a cell's death, while other "survival" proteins act to prevent programmed cell death.
One hallmark of cancer is that an excess of anti-death or survival proteins overwhelms the system when it is trying shut down the abnormal cell, causing the cell to reproduce, dangerously out of control, when it should be dying.
The pro-death part of the apoptosis toolbox includes a number of molecules known as BH3-only proteins. To ensure that cells destroy th
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Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
2-Sep-2004