Dokument: Is timing essential in cancer chronotherapy? Circadian molecular and behavioral studies on radiotherapy of hepatocellular carcinoma in mice
| Titel: | Is timing essential in cancer chronotherapy? Circadian molecular and behavioral studies on radiotherapy of hepatocellular carcinoma in mice | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=55607 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20210305-075347-6 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Hassan, Soha Abdelaliem Hassan [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. von Gall, Charlotte [Gutachter] Prof. Dr. Korf, Horst-Werner [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Radiotherapy is rarely used in the management of the HCC due to lacking trail data which supports the safety and efficacy of the radiotherapy and the increased risk of radiation-induced liver damage (RILD) which follows the hepatic radiotherapy. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiotherapy by considering timing of treatment. Ki67 (indicator for proliferation rate) and γ-H2AX (indicator for DNA-double strand breaks) are two important cell cycle components which can be used to predict the response of HCC to the radiotherapy. The main aim of this thesis is to introduce the concept of chronotherapy to radiobiological cancer research by identifying an optimal time point at which HCC is increasingly susceptible, whilst the surrounding healthy liver (HL) tissue becomes increasingly resistant to the damaging effects of cancer therapy.
This thesis showed significant differences in proliferation rate, DNA damage and repair mechanisms and expression of core clock genes between HCC and surrounding HL using two different experimental mouse models for hepatocellular carcinoma (double transgenic c-myc/TGFα and transgenic Per2::luc mice). The results support the concept of chronotherapy of HCC. Therefore, we investigated the effect of irradiation at four different time points of the day in transgenic Per2::luc mice bearing HCCs using Ki67 and γ-H2AX in in vitro samples from organotypic slice culture (OSC) and ex vivo samples. The results revealed time-dependent changes in the effect of radiotherapy on the proliferation rate, DNA damage and repair mechanisms and clock genes in HCC and surrounding HL. We concluded that ZT20 (late activity phase) is the optimal time point at which the HCC was more sensitive to radiotherapy (94.3% decrease in the proliferation rate), whilst the surrounding HL was more resistant to irradiation (lesser effect on the proliferation rate and DNA damage and repair mechanism as well as no effect on the core clock genes and total number of leukocytes) in the investigated model, although the animals irradiated at this ZT revealed more rhythm instability and stress. The chronotherapeutic approach for treatment of HCC may be an effective strategy to reduce the RILD. Unfortunately, OSC is not an ideal model to test the chronotherapeutic approach which needs studies with whole animals but OSC can be useful to determine dose-dependent effects. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 05.03.2021 | |||||||
| Dateien geändert am: | 05.03.2021 | |||||||
| Promotionsantrag am: | 17.12.2020 | |||||||
| Datum der Promotion: | 23.02.2021 |
