Proteasominhibition als neues Therapiekonzept

Zusammenfassung

Das Ubiquitin-Proteasom-System ist ein zentraler Mechanismus zum Abbau nicht mehr benötigter oder fehlerhafter zellulärer Proteine. Nach Markierung der Zielproteine mit Ketten aus dem Polypeptid Ubiquitin können diese Proteine vom sog. 26S-Proteasom zerstört werden. Die Hemmung dieses Systems durch kleine Moleküle hat vielfältige Auswirkungen auf die Zellproliferation. Präklinische und klinische Studien mit Proteasominhibitoren haben die Sicherheit und Wirksamkeit dieser neuartigen Therapieoption für maligne Erkrankungen eindrucksvoll belegt. Die erste zugelassene Substanz Bortezomib scheint die größte Wirkung beim Multiplen Myelom zu entfalten, hat sich aber auch bei anderen Non-Hodgkin-Lymphomen als effektiv erwiesen. Hervorzuheben ist die Fähigkeit von Proteasominhibitoren, in Kombination mit Chemotherapeutika eine Chemoresistenz zu durchbrechen. Durch Integration von Bortezomib in Induktions-, Erhaltungs- oder Rezidivtherapien scheinen bestehende Behandlungskonzepte entscheidend weiterentwickelt werden zu können. Ziel ist dabei, ein verbessertes Behandlungsergebnis mit geringen oder tolerablen Nebenwirkungen zu erreichen.

Abstract

The ubiquitin-proteasome-pathway is a central mechanism in degrading regulatory or damaged proteins in living cells. Target proteins tagged with polyubiquitin-chains are recognized and rapidly degraded by the 26 S proteasome. The inhibition of this pathway by small molecule inhibitors interferes with cell proliferation in multiple ways. Pre-clinical and clinical studies with proteasome inhibitors impressively demonstrated the safety and efficiency of this new therapeutic option for malignant diseases. The first approved substance bortezomib seems to be most effective in multiple myeloma and some other non-Hodgkin lymphomas. The ability of proteasome inhibitors in combination with chemotherapy to overcome chemoresistance can also be effective in other malignancies, such as solid tumors. The integration of bortezomib in induction, consolidation and salvage therapies seems to significantly improve current treatment options. The ultimate goal is to achieve optimal tumor regression with minimal or tolerable side effects.

Schlüsselwörter

Proteasominhibition - Ubiquitin - Multiples Myelom - Zellzyklus - Bortezomib

Key words

Proteasome inhibition - Ubiquitin - multiple myeloma - cell cycle - bortezomib

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