Auswirkungen von chemotherapeutischem Stress auf die Struktur und die Funktion des Nukleolus
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Diplomarbeit aus dem Jahr 2008 im Fachbereich Biologie - Genetik / Gentechnologie, Note: 1.0, Ludwig-Maximilians-Universität München (Institut für klinische Molekularbiologie und Tumorgenetik), Sprache: Deutsch, Abstract: Zytostatika werden seit über 50 Jahren erfolgreich zur Behandlung von Krebserkrankungen eingesetzt. Im Detail ist allerdings unklar, welche zellulären Prozesse beim Einsatz von Zytostatika betroffen sind. Diese Arbeit zeigt, dass man die rRNA-Synthese, und damit die Hauptfunktion des Nukleolus, mit einer Reihe zytostatisch wirksamer Substanzen hemmen kann. Es gibt prinzipiell zwei Arten der Hemmung, die Transkriptions- oder die Prozessierungshemmung. Als besonders wirksame Zytostatikaklassen lassen sich die Interkalantien (Transkriptionshemmer) sowie die Kinaseinhibitoren und die Translationsinhibitoren (Prozessierungshemmer) definieren. Sie hemmen die rRNA-Synthese spezifisch, vollständig und zum Teil nicht-genotoxisch. Eine blockierte rRNA-Synthese führt zu mehreren definierbaren zellulären Stressantworten. Die Mehrheit der wirksamen Substanzen erzeugt eine Disintegration des Nukleolus, die einhergeht mit der Translokation nukleolärer Proteine (Nukleophosmin, Pescadillo1, Fibrillarin) aus dem Nukleolus sowie der Induktion von p53. Ausgewählte Substanzen sind auch in Kombinationen auf rRNA-Synthesehemmung und p53-Induktion getestet worden. Dabei konnten sowohl additive wie synergistische Phänomene bei der Hemmung der rRNA-Synthese nachgewiesen werden. Die Kombination aus 5-FU und Flavopiridol ist von besonderem Interesse, da sie neue Perspektiven zur Erforschung der molekularen rRNA-Synthesemechanismen aufzeigt und gleichzeitig Anreize zur Verbesserung klinischer Therapieschemata bietet. Die Kinaseinhibitoren an sich stellen eine interessante Zytostatikaklasse dar. Mit ihnen lassen sich eine überschaubare Anzahl nukleolärer Kinasen hemmen, was zu einer starken Hemmung der rRNA-Prozessierung führt. Spezifische nukleolärer Kinasen könnten deshalb al
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