Radiobiological evaluation of established Glioblastoma multiforme cell lines as preclinical models in mice


Radiobiological evaluation of established Glioblastoma multiforme cell lines as preclinical models in mice

Jakob, A.; Linge, A.; Löck, S.; Thames, H. D.; Baumann, M.; Krause, M.; von Neubeck, C.

Less than 5 % of the patients diagnosed with the brain tumor Glioblastome multiforme (GBM) survive more than three years despite an intense therapy of surgery, radiation and application of the chemotherapeutic drug temozolomide (TMZ). The poor outcome underlines a need for the development of new treatment strategies which depends on the availability of suitable preclinical models. Here, we present results of the establishment and characterization of GBM models for the use in radiobiological research.
Basic in vitro investigations on the 5 GBM cell lines HGL21, LN-229, A7, U-251 MG and U-87 MG demonstrated radioresistance. The surviving fractions at a dose of 2 Gy X-rays ranged from 55 % (U-87 MG) to 85 % (A7). Administration of combined treatment with TMZ changed the cell survival in accordance to the methylation status of the MGMT promotor. Highly methylated cell lines LN-229, U-251 MG and U-87 MG showed the strongest response to TMZ.
Subcutaneous engraftment in nude mice further confirmed an aggressive character of the models.
High take rates for all cell lines were determined by means of the limiting dilution assay. Take doses 50 % , which indicate the cell number necessary to induce tumors in half of the animals, are in the range of 22 (HGL-21) to 187 (U-87 MG) cells reflecting a high content of stem-like cells. In contrast, extensive tumor control dose experiments of single dose treatment under hypoxic or ambient blood flow with or without combination with TMZ did not confirm the radioresistant phenotype. The tumor control doses 50 % (TCD50) ranked between 30 - 40 Gy under hypoxic conditions with the exception of U-87 MG (58 Gy). Additional treatment with TMZ decreased the TCD50 dramatically in 3 (LN-229, A7, U-87 MG) out of 4 models to values below 25 Gy.
Although the models partly mimic the clinical GBM characteristics, the radioresistance measured in vitro does not translate to the in vivo situation. As the models should mirror the clinical situation closely, their suitability for preclinical studies remains questionable.

  • Lecture (Conference)
    Young Scientist Forum 2016, 24.11.2016, Poznan, Poland, Poland

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Publ.-Id: 24161