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New drug target might sidestep gleevec resistance, Jefferson scientists show

(PHILADELPHIA) -- Though enormously successful, the leukemia drug Gleevec has some downsides. Recent studies have linked the drug to heart failure in a small number of patients, and drug resistance continues to be a problem. But now, researchers at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia may have found a new way to sidestep such resistance. They have discovered that by reactivating a protein that is normally shut off in leukemia and in Gleevec-resistant cancer cells, leukemia development is halted.

A drug that could turn on the gene that makes the protein C/EBP-alpha, a "transcription factor" required for cells to differentiate, then, might control or even eliminate the cancer.

According to Bruno Calabretta, M.D., Ph.D., professor of cancer biology at Jefferson Medical College of Thomas Jefferson University, transcription factors are molecular switches that turn on genes when their function is needed. C/EBP-alpha expression is low in leukemia cells such as those with the BCR-ABL protein defect, which causes chronic myeloid leukemia (CML), a disease that Gleevec treats so well.

Gleevec is normally prescribed for patients early on in CML, which is characterized by an overabundance of white blood cells. But when the disease advances to the terminal stage, or "blast crisis" phase, the cells, called blasts, remain undifferentiated and accumulate rather than becoming more mature white blood cells called granulocytes. Gleevec is much less effective in this stage, Dr. Calabretta says. Yet, in leukemia cells that respond to treatment with Gleevec, expression of C/EBP-alpha increases.

The researchers looked at what might happen if C/EBP-alpha was turned back on in blast crisis patients and in CML patients who were resistant to Gleevec. Reporting in the journal Blood, they found that in both the laboratory and in mice, immature white blood cells began to differen
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Contact: Steve Benowitz
steven.benowitz@jefferson.edu
215-955-5291
Thomas Jefferson University
15-Sep-2006


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