Reppingen, Norman (2018)
Pharmacological Augmentation of Heavy Ion Cancer Therapy.
Technische Universität Darmstadt
Ph.D. Thesis, Primary publication
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PhD Thesis from Norman Reppingen -
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Item Type: | Ph.D. Thesis | ||||
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Type of entry: | Primary publication | ||||
Title: | Pharmacological Augmentation of Heavy Ion Cancer Therapy | ||||
Language: | English | ||||
Referees: | Durante, Prof. Dr. Marco ; Thiel, Prof. Dr. Gerhard | ||||
Date: | 2018 | ||||
Place of Publication: | Darmstadt | ||||
Publisher: | TUprints | ||||
Date of oral examination: | 6 September 2017 | ||||
Abstract: | Tremendous progress is currently achieved in treating cancer, including the fields of radiother- apy, immunotherapy and pharmacology. Mechanisms of therapy methods on the one hand and treatment resistance mechanisms are increasingly elaborated, allowing to design combined treatment approaches which address the tremendous therapeutic challenges still imposed by many cancerous diseases. This also applies to heavy ion cancer therapy, which is very effec- tive as a single modality treatment, but remains a localized treatment with unclear systemic effects. On the cellular level, changes of phenotype could render tumor cells more visible to the immune system, as part of the response to radiation and by pharmacological mechanisms. In this thesis, we are looking at phenotype changes of murine tumor cell lines CT26.WT, 4T1 following x-ray and carbon ion irradiation as well as specific inhibition of c-Met, MEK and Akt, in order to gain mechanistic insights. Three pharmacological agents are evaluated, which did already show beneficial immune modulatory effects: Chloroquine, CDDO-Me and XL-184 (cabozantinib). Therefore, it is hypothesized here that the immune stimulatory properties seen in different models by others could act synergistically, as the mechanism(s) of activity of each compound are different and therefore most likely non redundant. In combination with carbon ion irradiation and x-ray an increase in apoptotic cell death was found in apoptotic cells, while carbon ion irradiation alone did rather lead to a necrotic (annexin-V negative) cell death. In an in vivo model for metastatic breast cancer (4T1) it is shown that XL184 does vastly reduce tumor growth. Conclusively, also heavy ion cancer therapy could potentially draw benefit from the pharmacological approach presented in this thesis, as the cell death mechanism and therefore the immunogenicity are potentially different. |
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URN: | urn:nbn:de:tuda-tuprints-77133 | ||||
Classification DDC: | 500 Science and mathematics > 500 Science 500 Science and mathematics > 530 Physics 500 Science and mathematics > 540 Chemistry 500 Science and mathematics > 570 Life sciences, biology 500 Science and mathematics > 590 Animals (zoology) 600 Technology, medicine, applied sciences > 610 Medicine and health |
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Divisions: | 10 Department of Biology | ||||
Date Deposited: | 21 Aug 2018 11:54 | ||||
Last Modified: | 09 Jul 2020 02:13 | ||||
URI: | https://tuprints.ulb.tu-darmstadt.de/id/eprint/7713 | ||||
PPN: | 435101315 | ||||
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