Expression HIF-1 abhängier Gene nach Inhibition von HIF-1α mittels Sirna in humanen Lungenadenokarzinomzellen und deren Regulation nach Photonen- und Kohlenstoffionenbestrahlung

Die Strahlentherapie spielt eine bedeutende Rolle in der Behandlung von Bronchialkarzinomen; Dabei gilt es Resistenzfaktoren zu erkennen und nach Möglichkeit zu umgehen. Für die Bestrahlung mit Photonen ist bekannt, dass Hypoxie zu Therapieversagen führen kann. Dies liegt zum einen an dem sogenannte...

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1. Verfasser: Westholt, Niklas
Beteiligte: Engenhart-Cabillic, R. (Prof. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Veröffentlicht: Philipps-Universität Marburg 2016
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Inhaltsangabe: Radiation therapy plays an important role in treatment of lung cancer. Hereby, it is helpful to identify and, if possible, avoid resistance factors. It is known that hypoxia can lead to failure of treatment in radiotherapy with photons. On the one hand, this is due to a so-called chemical oxygen effect, which refers to a reduced formation of free radicals. On the other hand, it is caused by the biological oxygen effect and thus an increased expression of HIF-1 and HIF-1 dependent genes. Further it is also known that the photon radiation itself leads to increased HIF-1 expression and therefore to radiation-induced radio resistance. In regard to radiation-induced radioresistance, this thesis reviewed the situations and underlying mechanisms leading to increased HIF-1 expression and the effect this has on HIF-1 dependent genes. Further, this work was concerned with the means of preventing radiation-induced radioresistance; More specifically, it studied the following three methods of avoiding radiation-induced radioresistance: 1. Irradiation with carbon ions 2. Inhibition of PI3K / AKT / mTOR signaling cascade 3. Degradation of the mRNA of HIF-1α by siRNA transfection In summary it could be shown that both hypoxia as well as irradiation with photons (but not with carbon ions) leads to increased expression of HIF-1 and the HIF-1 dependent genes. Furthermore, it was shown that this could be due to activation of the PI3K / AKT / mTOR signaling cascade. Ultimately, it was also shown that all three methods to bypass an increased radio resistance in our in vitro system were suitable to prevent the overexpression of HIF-1 and HIF-1 dependent genes. On the one hand, cells which were irradiated with carbon ions did not show increased HIF-1 expression. On the other hand HIF-1 however does not play a major role in treatment with carbon ions. The inhibition of the PI3K / AKT / mTOR signaling pathway with rapamycin prevents induction of HIF-1 by photon irradiation and can circumvent a radiation-induced radio resistance. And furthermore transfection with siRNA can reliably prevent high HIF-1 expression and thereby possibly prevent an increased radiation resistance. To decide whether such methods are suitable for the use on humans, further research is necessary. Especially carbon ion irradiation has yet to be researched until patients can benefit from this in a regular therapy regimen and with the best possible outcome. However, it can be said that this is a promising method to overcome treatment failure in photon radiation. Furthermore the administration of rapamycin is already used in clinical practice under other conditions and could potentially contribute to higher treatment success rates. But it remains unlikely whether siRNA transfection can be performed in the human body.