Resistenz von Brust- und Ovarialkarzinom-Zellen gegenüber Chemotherapeutika in Abhängigkeit von der Expression des HER-2 neu-Rezeptors

Der HER-2-Rezeptor, ein Tyrosinkinase-Rezeptor aus der ”Epidermal Growth Factor Receptor” (EGFR)-Familie, gilt in Brustkarzinomen als wichtiger Marker für ein aggressiveres Tumorwachstum, ein erhöhtes Metastasierungs-Potential und eine gesteigerte Chemoresistenz gegenüber verschiedenen Zytostatika....

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Bibliographic Details
Main Author: Apel, Jürgen Johannes
Contributors: Czubayko, Frank (Prof. Dr. med) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2005
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The HER-2 neu-receptor is a tyrosinkinase- receptor of the "epidermal growth factor receptor"- family (EGFR). In breast cancer it is an important marker for an aggressive tumor growth, an elevated risk of metastasis and a higher resistance towards chemotherapeutic agents. Ovarian carcinoma, which often show an over-expression of HER-2 neu-receptor, have a very low chemotherapeutic sensitivity and are associated with a fast development of chemotherapeutic resistance. The influence of HER-2 neu expression on chemo-resistance in ovarian cancer cells is not yet investigated in detail. In this work we wanted to analyse the importance of HER-2 neu over-expression in breast- and ovarian cancer cells on resistance to various cytostatic drugs. Therefore the HER-2-receptor expression was inhibited by ribozym-targeting and a following clonal selection in SKOV-3 ovarian carcinoma cells. In MCF-7 breast cancer cells we used the overexpression of HER-2-ECD (a dominant negative receptor mutante) as a HER-2-receptor antagonism. We could demonstrate an influence of HER-2-ECD expression levels on chemotherapeutic sensitivity in breast cancer cells to chemotherapy with Paclitaxel and Topotekan. This could be explained by changes in cell cycle progression in Paclitaxel treatment depending on HER-2-ECD-levels. In SKOV-3 ovarian carcinoma cells we demonstrated a HER-2-gene dose dependence on chemo-sensitivity towards Paclitaxel and Topotekan by clonal selection. Interestingly this dependence is directed contrary to that of breast cancer cells. Important changes in cell cycle progression and induction of apoptosis were found to explain the dependence of HER-2-receptor expression in ovarian carcinoma cells and the resistance towards these cytostatic drugs. The treatment of ovarian carcinoma cells with Doxorubicin and Cisplatin as well as that of breast cancer cells with Vinblastin and Cisplatin was not influenced by HER-2 neu-receptor expression. In order to analyse whether the principle of action of the cytostatic drugs is of eventual importance concerning the HER-2 dependent chemo-resistance we used rViscumin, a cytostatic drug acting by a completely different mechanism. We clearly showed that the chemo-resistance of SKOV-3 ovarian carcinoma cells to rViscumin was altered by different HER-2-receptor expression levels, similar to the treatment with Paclitaxel and Topotekan. We could again find significant changes of apoptosis induction leading to an increased chemo-resistance depending on HER-2-receptor expression. This work showed that the chemo-resistance of MCF-7 breast carcinoma cells and SKOV-3 ovarian carcinoma cells towards some cytostatic drugs is dependent on HER-2 neu-receptor expression levels. Moreover it became obvious that this alteration of chemo-resistance is drug and cell line specific and that the principle of action of the cytostatic drug does not seem to be of major importance.