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Unusual three-drug combo inhibits growth of aggressive tumors

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They combined these two drugs with a third drug, flumazenil, which is ordinarily used to reverse the effects of sedatives. Flumazenil binds to GABA receptors on the surface of nerve cells, and the researchers theorized that it could also inhibit GABA signaling between tumor cells.

The amiloride-carbidopa-flumazenil combination was administered to mice that had prostate neuroendocrine tumor cells implanted beneath their skin. Compared to mice that didn't receive the drug therapy, those treated with the combination had 40 percent less tumor growth.

"We propose that this might be a potential therapeutic regimen for patients with aggressive neuroendocrine tumors," says Ippolito. "Since the drugs are already FDA approved, they could be more quickly used as experimental therapeutics."

Examination of gene expression profiles of more than 400 human cancers showed that the genes encoding the enzymes vital to these aggressive neuroendocrine tumors were also expressed at high levels in some non-neuroendocrine cancers. This suggests that the three-drug therapy could work for many kinds of cancers, according to the study authors.

"This approach is very powerful," says Gordon. "By combining a variety of experimental and computational methods that monitor the expression of genes encoding enzymes and their biochemical products, we can explore the metabolism of these cells, looking for unusual pathways that might reveal their potential vulnerabilities. Then we can see if medications already exist - ones whose mechanism of action is known and whose safety has been established - that can be used to target components of these unusual pathways, test them in animal models of human cancer, and if the results look promising, bring them to the patient's bedside as part of a carefully controlled clinical trial."


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Contact: Gwen Ericson
ericsong@wustl.edu
314-286-0141
Washington University School of Medicine
7-Sep-2006


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