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A circuitous route to therapy resistance
Date:6/26/2013

Gliomas are malignant brain tumors that arise from glial cells called astrocytes, found in the central nervous system. "In treating malignant gliomas, we currently combine radiotherapy with the anticancer drug temozolomide. However, in some patients, tumors rapidly become resistant to both treatment methods," says neurooncologist Professor Dr. Michael Platten, who leads a cooperation unit of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Department of Neurooncology of Heidelberg University Hospital. "We therefore urgently need new methods of treating these diseases more effectively."

Chemotherapy and radiotherapy damage the DNA of tumor cells. Normally these DNA defects automatically trigger the cellular suicide program known as apoptosis. However, tumor cells possess an efficient DNA repair system that they use to protect themselves from the consequences of therapy, thus evading cell death.

Key repair mechanisms in the cell can only work efficiently if a molecule called NAD+ is present. When DNA repair is running at full throttle, as is the case during radiation therapy, NAD+ supplies are quickly exhausted in a cancer cell, leading to DNA damage that goes unrepaired and ultimately cell death. Cancer researchers are therefore trying to use drugs to deprive cells of NAD+ to prevent resistance to therapies. Substances that inhibit the enzyme which produces NAD+ are already being tested in clinical trials.

However, cells can produce NAD+ in a number of ways. They can synthesize it directly, or use a substance called quinolinic acid, a metabolite of the protein building-block tryptophan, as an alternative source to produce NAD+. Michael Platten and his team had discovered that malignant gliomas contain large amounts of quinolinic acid. "We wanted to know whether gliomas might use this circuitous route in order to produce enough NAD+ and thus escape therapy," says neuropathologist Felix Sahm, first au
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Contact: Dr. Sibylle Kohlstädt
s.kohlstaedt@dkfz.de
Helmholtz Association of German Research Centres
Source:Eurekalert

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