Artikel
Augmentation of Tumor Treating Fields (TTFields) effects on Glioblastoma cells by mitotic checkpoint inhibition
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Autoren
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Almuth F. Keßler
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
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Franziska Gross
- Universitätsklinikum Würzburg, Tumorbiologisches Labor, Neurochirurgische Klinik und Poliklinik, Wuerzburg, Deutschland
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Mirja Hahn
- Universitätsklinikum Würzburg, Tumorbiologisches Labor, Neurochirurgische Klinik und Poliklinik, Wuerzburg, Deutschland
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Thomas Linsenmann
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Department of Neurosurgery, Würzburg, Deutschland
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Ralf-Ingo Ernestus
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
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Mario Löhr
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
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Carsten Hagemann
- Universitätsklinikum Würzburg, Neurochirurgische Klinik und Poliklinik, Neurochirurgische Klinik und Poliklinik, Würzburg, Deutschland
| Veröffentlicht: | 9. Juni 2017 |
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Gliederung
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Objective: Treatment of glioblastoma (GBM) patients with Tumor Treating Fields (TTFields) in addition to standard therapy showed significant increase in progression free and overall survival (EF-14 trial). TTFields are alternating electric fields with low intensity (1-3V/cm) and intermediate frequency (100-400kHz) that disrupt cell division through the inhibition of spindle fiber formation. The chemotherapeutic agent Vincristine also inhibits spindle fiber formation but in contrast to TTFields, Vincristine therapy is associated with severe side effects. The spindle assembly checkpoint (SAC) diminishes the therapeutic effects of spindle damaging agents by monitoring the correct segregation of sister chromatids. Monopolar spindle 1 (MPS1), the key regulator of SAC, when combined with Vincristine shows a synergistic effect on GBM growth in mice. Therefore, MPS1 inhibition could increase the efficacy of TTFields.
Methods: Utilising the Novocure inovitro™ laboratory research system, 30,000 human GBM U87 cells were treated with TTFields (200kHz) alone or with 4µM of the MPS1 inhibitor MPS1-IN-3 (IN3) either alone or in combination with TTFields. Cell numbers and apoptosis (Annexin V staining) were evaluated after 24h, 48h and 72h of treatment. Cell numbers were also evaluated at 24h and 72h after end of treatment (eot).
Results: Treatment with TTFields plus IN3 resulted in an earlier response. After 72h, the cell number decreased by 77.5% compared to TTFields alone (P = 0.0201) and by 50% compared to MPS1-inhibition with IN3 (p = 0.0344). While the cells treated with TTFields alone decreased for another 24h after eot and then started to recover, the combination of TTFields and IN3 resulted in a decrease of cell numbers by a further 92% at 72h after eot of TTFields (p = 0.0086). All cells recovered in instances when IN3 treatment ended after 72h. The combination treatment of TTFields plus IN3 induced an early stage of apoptosis in 44% of the cells, compared to 14% with TTFields alone (p = 0.0002) and 4% with IN3 alone (p < 0.0001).
Conclusion: TTFields are an approved new treatment modality for GBM. A combination of physically damaging the spindle apparatus by TTFields and the chemical inhibition of the SAC led to earlier and prolonged effects, which significantly augment TTFields efficacy..
