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New use for a cell toxin found to inhibit survival proteins in cancer cells

SEATTLE A chemically-modified version of a mitochondrial toxin long used to control species of invasive fish in lakes has been found to selectively inhibit two "survival proteins in cancer cells. The research is a first step toward developing a molecularly-targeted drug that could eliminate cellular-level resistance to multiple types of chemotherapy and radiation therapy found in many types of cancers.

In a paper published today in the July 2007 issue of Molecular Cancer Therapeutics, scientists at Fred Hutchinson Cancer Research Center report that a modified version of antimycin called 2-Methoxy antimycin is selective in killing cells that have high levels of Bcl-2 and Bcl-xL proteins. The over expression of these proteins in many types of cancer cells correlates with resistance to chemotherapy and radiation therapy. Cells with normal levels of Bcl-2 or Bcl-xL are resistant to 2-Methoxy antimycin.

David M. Hockenbery, a member of the Hutchinson Centers Clinical Research Division and principal investigator for the study, and colleagues set up screening assays to look for small molecules or compounds that are selectively toxic to cells that over express Bcl-2 proteins. Higher expression of the target protein made cells more sensitive to the 2-Methoxy antimycin inhibitor. This is called a gain of function mechanism and is counterintuitive to the way most drugs work.

Our compound, 2-Methoxy antimycin, is the only Bcl-2 inhibitor reported with gain of function activity, which provides a therapeutic window between cancer cells with high expression of the proteins versus cells with normal expression, said Hockenbery, who is also a professor of medicine at the University of Washington Medical Center. This effect was preserved when 2-Methoxy antimycin was used in combination with other agents, and could lead to a targeted molecular therapy to enhance the effectiveness of cancer treatments.

Hockenbery said his groups approach illustrated the need
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Contact: Dean Forbes
dforbes@fhcrc.org
206-667-2896
Fred Hutchinson Cancer Research Center
11-Jul-2007


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