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March 15, 2004
March 15, 2004
A drug widely used to prevent nausea and other side effects in patients receiving chemotherapy for breast cancer may also, unfortunately, prevent the therapy from working efficiently on tumor cells, researchers from the University of Chicago report in the March 1 issue of the journal, Cancer Research.
Dexamethasone--a synthetic steroid--is routinely given to women just before they receive chemotherapy with either paclitaxel or doxorubicin, two drugs commonly used to treat breast cancer. In this laboratory study, the researchers show that pretreatment with dexamethasone reduces the ability of paclitaxel and doxorubicin to kill cancer cells.
"Nearly every patient receiving chemotherapy for breast cancer also receives dexamethasone pre-treatments that may make therapy less effective," said Suzanne Conzen, MD, assistant professor of medicine at the University of Chicago and director of the study. "With breast cancer one wants the best tumor reduction possible, but we have evidence that the benefits provided by routine treatment with dexamethasone may cause decreased chemotherapy-induced tumor cell death."
Conzen's team became suspicious nearly four years ago when they discovered that a group of steroid hormones know as glucocorticoids could inhibit death in certain cell types, including breast epithelial cells. This made them begin to question the wisdom of treating breast cancer patients with dexamethasone (known as Dex), an artificial glucocorticoid.
A careful search of the literature on dexamethasone uncovered another surprise. "Remarkably," the authors note, no clinical studies had ever addressed the potential effects on tumor response of administering Dex before routine chemotherapy for breast cancer.
To study these effects at the molecular level, Conzen's team devised a laboratory system that mimicked the usual clinical administration of dexamethasone in this setting. They found that pretreatment of breast cancer cells 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 Chicago. The National Institutes of Health, the Department of Defense, the Schweppe, Concern, Entertainment Industry, and the University of Chicago Cancer Research Foundations supported the research.