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Widely used anti-nausea drug may interfere with cancer chemotherapy

lls with dexamethasone reduced the cell death rate following exposure to either paclitaxel or doxorubicin by more than 25 percent, even though the two drugs rely on very different mechanisms to cause tumor cell destruction.

Since dexamethasone actually kills certain types of cells such as lymphocytes and is effective treatment for lymphoma, the researchers wondered why Dex destroys one type of cancer cell yet protects another from cell death. Using a technique that measures the effects of a drug on gene expression, they found that dexamethasone consistently upregulated 45 genes in breast cancer cells and that these genes differed from those found to be regulated by dexamethasone in earlier studies using lymphocytes.

They then focused their attention on two genes that were upregulated in breast cells by dexamethasone -- SGK-1 and MKP-1. SGK-1 has been previously shown to prevent cell death in brain and breast cells. MKP-1 can protect prostate cancer cells and its increased expression is associated with breast, ovarian and pancreatic cancers.

They found that both SGK-1 and MKP-1 played a major role in dexamethasone's effects, protecting breast cancer cells from the effects of both paclitaxel and doxorubicin. Blocking these proteins, on the other hand, reversed the drug's unwanted effects on cancer cell survival.

Although the authors are not yet ready to stop using dexamethasone, a very effective drug for prevention of side effects from chemotherapy, Conzen suggests that the evidence is mounting that oncologists "should begin to study the effects of using this drug routinely as part of breast cancer therapy."

"The widespread use of drugs such as dexamethasone before chemotherapy," the authors conclude, "requires reevaluation because of the observed inhibition of chemotherapy efficacy."

Additional authors of the study were Wei Wu, Shamita Chaudhuri, Deanna Brickley, Diana Pang and Theodore Karrison of the University of
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Contact: John Easton
jeaston@uchospitals.edu
773-702-6241
University of Chicago Medical Center
2-Mar-2004


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