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Turkish Journal of Cancer
2009, Volume 39, Number 3, Page(s) 104-109
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Valproic acid as a potent substance for increasing efficacy of topoisomerase I inhibitors
Sabine Wagner1, Stefaan Van Gool2, Peter Hau3, Thorsten Pietsch4, Ove Peters1, Johannes Wolff1,5
1University of Regensburg, Krankenhaus der Barmherzigen Brüder Klinik St. Hedwig, Department of Pediatric Oncology, Regensburg-Germany
2University Hospital Gathuisberg, Department of Pediatric Oncology, Leuven-Belgium
3University of Regensburg, Bezirksklinikum, Department of Neurology, Regensburg-Germany
4University of Bonn, Institut für Neuropathologie, Bonn-Germany
5University of Texas, MD Anderson Cancer Center, Department of Pediatrics, Houston, TX-USA

Valproic acid (VPA) is a small molecule originally licensed as epilepsy drug, but then discovered as histone deacetylase inhibitor and anticancer drug. Topotecan is a chemotherapeutic drug, which functions as topoisomerase I inhibitor and has shown antiglioma efficacy in clinical trials. Here we tested the combination of these two agents in cultured glioma and medulloblastoma cells. 100μl of U87MG high grade glioma cells and MED 283 medulloblastoma cells were plated with 3000 cells/well in 96 well plates. After 24 hours drugs were added. VPA was used in concentration of 0.7, 1.4, 3.5 mM, topotecan was diluted 0.02 nM to 14.8 nM, with an incubation time of 72 and 120 hours. MTT-tests were used for measuring cell viability. VPA at concentration of 3.5 mM increased cell proliferation by 10 to 20%, 0.7 mM had no effect on cell proliferation, and higher concentrations reduced the cells numbers. The IC50 of three days VPA was 13.9 mM. Topotecan incubation was cytotoxic. The IC50 of topotecan (three days) was 0.9 nM. When both drugs were given together, the cytotoxicity was higher: with a constant concentration of dose of 0.7 mM VPA the IC50 of topotecan was only 0.5 nM. The same effect was seen with 1.4 mM VPA. Incubation with 3.5 mM VPA over 72 h enhanced the reduction of cell viability, the IC50 of topotecan and valproic acid was 0.2 mM. The effect became further enhanced, when increasing the incubation time. A combination treatment of the histone deacetylase inhibitor VPA and topotecan, enhanced the antitumor efficacy of the topoisomerase-I-inhibitor. [Turk J Cancer 2009;39(3):104-109]

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