DD-06 * POTENTIATING THE THERAPEUTIC EFFICIENCY OF THE ALKYLATING CHEMOTHERAPY TEMOZOLOMIDE IN PATIENTS WITH GLIOBLASTOMA

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Glutamate is the most prominent excitatory neurotransmitter of the brain. Due to its pivotal role, deregulations of the glutamate metabolism have been implicated in various CNA diseases. System xc- (SXC), an L-cystine/L-Glutamate antiporter represents the primary non-vesicular route of glutamate release. SXC is upregulated under amino acid deprivation, xenobiotic exposure and oxidative stress. GBM depends on L-cystine influx by SXC activity, to uphold a sufficient Glutathione level. Glutathione is a neuroprotective peptide involved in removal of xenobiotics, like therapeutic drugs. L-cysteine is essential for its synthesis. SXC is highly expressed in Glioblastoma Multiforme (GBM), the most common type of brain malignancy with a median survival of only 14 months. GBM has proven to be highly resistant to therapy. Thusly, potentiating the efficacy of Temozolomide by blocking SXC might lead to an increase in median survival. We are investigating expression of SXC in GBM -in surgical specimen and patient derived cell lines- and the effect of Sulfasalazine (SSZ) on cell survival. SSZ is a FDA-approved SXC antagonist. SXC expression in surgical specimen of GBM and thereof derived cell lines was investigated on mRNA and protein level. Since our results reaffirmed expression of SXC, cell lines were treated in vitro with either SSZ, TMZ or concomitantly. Concomitant treatment resulted in a continuous decrease in viability over the course of 30 days. Survival was significantly decreased when compared to control, SSZ or TMZ alone, without any rescue efffect. In conclusion, the evidence shows a strong correlation between prolonged survival and concomitant use, suggesting a heightened sensitivity to chemotherapy, conveyed by blocking of the system xc- antiporter. Thusly, pharmacokinetics of SSZ have been analysed to assess brain penetration. In future work, the efficacy of concomitant treatment with SSZ and TMZ will be evaluated in vivo to indicate whether there would be any clinical utility.