Der Gentransfer normaler Tumorsuppressorgene, die bei einer Vielzahl humaner Tumoren verändert sind, ermöglicht die Behandlung neoplastischer Zellen durch Hemmung von Zellproliferation und Induktion von Apoptose. Arbeiten der letzten Jahre lieferten entscheidende Erkenntnisse zur Funktion von Tumorsuppressorproteinen als negative Regulatoren von Zellproliferation und Tumorentwicklung und ihrer Beteiligung an komplexen biochemischen Signaltransduktionswegen. Tumorzellen weisen sehr häufig eine Schädigung der Gene auf, die direkt an der Regulation des Zellzyklus beteiligt sind. Dabei gehören Mutationen im RB-Signalweg (D-Zykline/CDKs/CDKIs/RB/E2F) zu den häufigsten Veränderungen in menschlichen Tumoren. Neben der Inaktivierung des Tumorsuppressors p53, betreffen die Veränderungen im RB-Weg das Retinoblastom (RB)-Protein und die Cyclin-abhängigen Kinasen (CDKIs) p16INK4a und p21WAF1. Derartige Alterationen sind verantwortlich für die erhöhte Zellteilungskapazität dieser Zellen und ihre Resistenz gegenüber herkömmlichen Therapien wie Radio- und Chemotherapie. Obwohl Tumoren noch weitere Veränderungen aufweisen, die an der Kontrolle der Zellproliferation beteiligt sind, kann der Austausch einer einzelnen spezifischen Alteration durch die Wildtyp-Tumorsuppressorfunktion ausreichen, um den Zelltod durch Apoptose zu induzieren. Es ist allerdings durch die gegenwärtig verfügbaren Methoden des In-vivo-Gentransfers nicht möglich, die normale Genfunktion in jeder Tumorzelle zu ersetzen. Daher sind Mechanismen, bei denen das in der transduzierten Zelle exprimierte Transgen das Wachstum nicht-transduzierter, benachbarter Zellen beeinflußt, sog. Bystander-Effekte, entscheidend für den Erfolg solcher Gentherapieansätze. Dieses Review gibt einen Überblick über die gegenwärtigen präklinischen und klinischen Untersuchungen zum Gentransfer von Tumorsuppressorgenen unter Verwendung adenoviraler Transfersysteme, diskutiert die Grenzen dieser Therapie und zeigt Perspektiven für zukünftige klinische Anwendungen auf.
Gene therapy using wild-type tumor suppressor genes which are frequently mutated in human cancers has the potential to provide cancer treatment based on cell growth retardation and induction of apoptosis in cancer cells. Over the past few years, significant insight has been gained regarding the functions of tumor suppressors and how they participate in the complex biochemical pathways governing the negative regulation of cell growth and tumor development. Tumor cells have typically acquired damage to genes that directly regulate their cell cycle. Mutations within the RB-pathway (D-cyclins/CDKs/CDKIs/RB/E2F) are the most frequent abnormalities identified in human cancers. Beside inactivation of the tumor suppressor protein p53, alterations in the RB-pathway frequently affect the retinoblastoma protein (RB) and the cyclin-dependent kinase inhibitors (CDKIs) p16INK4a and p21WAF1. These alterations are responsible for the enhanced proliferative capacity and resistance of the cells to commonly used therapies such as radio- and chemotherapy. Although all cancers contain multiple abnormalities apart from the RB-pathway controlling various aspects of cellular proliferation, correction of a single specific molecular alteration by reintroduction of wild-type tumor suppressor function, in some cases is sufficient to induce tumor cell death by apoptosis. However, it is beyond the capabilities of currently available methods for in vivo gene transfer to restore normal gene function in every cancer cell. Therefore, mechanisms by which a toxic transgene expressed in transduced cells can alter growth of non-transduced cells, by a so called bystander effect is essentially important for successful gene replacement strategies. This review summarizes current preclinical and clinical efforts on gene replacement approaches with adenoviral gene delivery systems, discusses limitations of therapy and highlights the prospects for future clinical investigations.
Schlüsselwörter:
Tumorsuppressorgene - Neoplasien - Gentherapie - Adenovirus Vektoren
Key words:
Tumor suppressor genes - Neoplasia - Gene therapy - Adenovirus vectors
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Dr. Brigitte Pützer
Institut für Molekularbiologie (Tumorforschung) Universitätsklinikum
Hufelandstr. 55
45122 Essen
Phone: 0201-723-3158/3153
Fax: 0201-723-5974
Email: brigitte.puetzer@uni-essen.de
