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Researchers break chain of biochemical events that brain cancer cells use to evade therapy

tion (reduction) of enzyme activity. With caspase-3 activation blocked, apoptosis is halted and cancer cells grow uncontrolled.

The Cedars-Sinai researchers theorized that a diabetes drug called troglitazone would limit the effects of the overexpressed proteins, reinstating the caspase activity and the process of apoptosis. In patient trials, pioglitazone will be used instead of troglitazone, which was the ingredient in Rezulin, removed from the market because of safety issues. Pioglitazone acts in cancer cells in the same way as troglitazone, but without the associated liver concerns. Both are in a family of drugs called thiazolidinediones, given in tablet form to patients with Type 2 diabetes to improve cells' responsiveness to insulin.

Although Yu and his colleagues usually are hesitant to prescribe more than one anti-cancer medication, this appears to be an ideal situation for a two-drug attack.

"When you combine two therapeutic agents, you usually get the toxicity of both, which is additive. But this strategy is different in that we are using a common diabetes drug that does not have the toxicity of a therapeutic agent. We have medications that are designed to induce apoptosis in tumor cells. Now we have a drug that appears to lower thresholds for induction of apoptosis," said Yu, senior author of a paper describing the study in the Journal of Biological Chemistry, published online Nov. 30, 2005. The article is expected to be published in the print version of the journal in late January.

"This study shows that as we begin to dissect the biochemistry of cancer, we can design therapies that interact within the critical pathways that are important for cancers to survive," said Keith L. Black, M.D., director of the Institute and the Division of Neurosurgery at Cedars-Sinai. "One of the things we have learned is that there probably will not be one ultimate pathway in cancer that we can block and be curative. A more likely scenario is
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Contact: Sandy Van
sandy@prpacific.com
800-880-2397
Cedars-Sinai Medical Center
3-Feb-2006


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