@article{FeldheimKesslerFeldheimetal.2022,
  author    = {Feldheim, Jonas and Kessler, Almuth F. and Feldheim, Julia J. and Schulz, Ellina and Wend, David and Lazaridis, Lazaros and Kleinschnitz, Christoph and Glas, Martin and Ernestus, Ralf-Ingo and Brandner, Sebastian and Monoranu, Camelia M. and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {Effects of long-term temozolomide treatment on glioblastoma and astrocytoma WHO grade 4 stem-like cells},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {9},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23095238},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284417},
  year      = {2022},
  abstract  = {Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O\(^6\)-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.},
  language  = {en}
}
@article{NicklSchulzSalvadoretal.2022,
  author    = {Nickl, Vera and Schulz, Ellina and Salvador, Ellaine and Trautmann, Laureen and Diener, Leopold and Kessler, Almuth F. and Monoranu, Camelia M. and Dehghani, Faramarz and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {Glioblastoma-derived three-dimensional ex vivo models to evaluate effects and efficacy of Tumor Treating Fields (TTFields)},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {21},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14215177},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290340},
  year      = {2022},
  abstract  = {Simple Summary In glioblastoma, tumor recurrence is inevitable and the prognosis of patients is poor, despite multidisciplinary treatment approaches involving surgical resection, radiotherapy and chemotherapy. Recently, Tumor Treating Fields (TTFields) have been added to the therapeutic set-up. These alternating electric fields are applied to glioblastoma at 200 kHz frequency via arrays placed on the shaved scalp of patients. Patients show varying response to this therapy. Molecular effects of TTFields have been investigated largely in cell cultures and animal models, but not in patient tissue samples. Acquisition of matched treatment-na{\"i}ve and recurrent patient tissues is a challenge. Therefore, we suggest three reliable patient-derived three-dimensional ex vivo models (primary cells grown as microtumors on murine organotypic hippocampal slices, organoids and tumor slice cultures) which may facilitate prediction of patients' treatment responses and provide important insights into clinically relevant cellular and molecular alterations under TTFields. Abstract Glioblastoma (GBM) displays a wide range of inter- and intra-tumoral heterogeneity contributing to therapeutic resistance and relapse. Although Tumor Treating Fields (TTFields) are effective for the treatment of GBM, there is a lack of ex vivo models to evaluate effects on patients' tumor biology or to screen patients for treatment efficacy. Thus, we adapted patient-derived three-dimensional tissue culture models to be compatible with TTFields application to tissue culture. Patient-derived primary cells (PDPC) were seeded onto murine organotypic hippocampal slice cultures (OHSC), and microtumor development with and without TTFields at 200 kHz was observed. In addition, organoids were generated from acute material cultured on OHSC and treated with TTFields. Lastly, the effect of TTFields on expression of the Ki67 proliferation marker was evaluated on cultured GBM slices. Microtumors exhibited increased sensitivity towards TTFields compared to monolayer cell cultures. TTFields affected tumor growth and viability, as the size of microtumors and the percentage of Ki67-positive cells decreased after treatment. Nevertheless, variability in the extent of the response was preserved between different patient samples. Therefore, these pre-clinical GBM models could provide snapshots of the tumor to simulate patient treatment response and to investigate molecular mechanisms of response and resistance.},
  language  = {en}
}
@article{SchulzMawambaLoehretal.2022,
  author    = {Schulz, Ellina and Mawamba, Viviane and L{\"o}hr, Mario and Hagemann, Carsten and Friedrich, Alexandra and Schatzschneider, Ulrich},
  title     = {Structure-activity relations of Pd(II) and Pt(II) thiosemicarbazone complexes on different human glioblastoma cell lines},
  series = {Zeitschrift f{\"u}r Anorganische und Allgemeine Chemie},
  volume    = {648},
  journal   = {Zeitschrift f{\"u}r Anorganische und Allgemeine Chemie},
  number    = {12},
  issn      = {0044-2313},
  doi       = {10.1002/zaac.202200073},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318281},
  year      = {2022},
  abstract  = {Ten thiosemicarbazone ligands obtained by condensation of pyridine-2-carbaldehyde, quinoline-2-carbaldehyde, 2-acetylpyridine, 2-acetylquinoline, or corresponding 2-pyridyl ketones with thiosemicarbazides RNHC(S)NHNH\(_{2}\) and R=CH\(_{3}\), C\(_{6}\)H\(_{5}\) were prepared in good yield. The reaction of [PdCl\(_{2}\)(cod)] with cod=1,5-cyclooctadiene or K\(_{2}\)[PtCl\(_{4}\)] resulted in a total of 17 Pd(II) and Pt(II) complexes isolated in excellent purity, as demonstrated by \(^{1}\)H, \(^{13}\)C, and, where applicable, \(^{195\)Pt NMR spectroscopy combined with CHNS analysis. The cytotoxicity of the title compounds was studied on four human glioblastoma cell lines (GaMG, U87, U138, and U343). The most active compound, with a Pd(II) metal centre, a 2-quinolinyl ring, and methyl groups on both the proximal C and distal N atoms exhibited an EC\(_{50}\) value of 2.1 μM on the GaMG cell lines, thus being slightly more active than cisplatin (EC\(_{50}\) 3.4 μM) and significantly more potent than temozolomide (EC\(_{50}\) 67.1 μM). Surprisingly, the EC\(_{50}\) values were inversely correlated with the lipophilicity, as determined with the "shake-flask method", and decreased with the length of the alkyl substituents (C\(_{1}\)>C\(_{8}\)>C\(_{10}\)). Correlation with the different structural motifs showed that for the most promising anticancer activity, a maximum of two aromatic rings (either quinolinyl or pyridyl plus phenyl) combined with one methyl group are favoured and the Pd(II) complexes are slightly more potent than their Pt(II) analogues.},
  language  = {en}
}