Anti-Angiogenese als Therapieprinzip in der gastroenterologischen Onkologie

Zusammenfassung

Der Prozeß der tumorassoziierten Angiogenese ist von zentraler Bedeutung für das lokale Tumorwachstum, seine Invasion und die nachfolgende Metastasierung. Die sehr komplexen Vorgänge beruhen auf vielen Einzelschritten, die sowohl von der lokalen Balance zwischen positiven und negativen Regulationsfaktoren, aber auch von den Interaktionen des Karzinoms mit seiner Gefäßversorgung und der umgebenden extrazellulären Matrix abhängig sind. Eine Vielzahl von angiogenen Faktoren wurde in den letzten Jahren identifiziert, charakterisiert und schließlich als therapeutische Zielstruktur definiert. Hierzu zählen u. a. Wachstumsfaktoren, die an die Rezeptor-Tyrosinkinasen binden. Zu den besonders wirksamen proangiogenen Wachstumsfaktoren zählt der vaskuläre endotheliale Wachstumsfaktor (VEGF). VEGF stimuliert hochspezifisch die Proliferation von vaskulären Endothelzellen. Die meisten antiangiogenen Substanzen modulieren die Aktivität endothelialer Zellen oder beeinflussen proangiogene Wachstumsfaktoren bzw. deren Rezeptor-Tyrosinkinasen. Insbesondere stellt die Blockade des VEGF/VEGF-Rezeptorsystems einen wichtigen und neuen Ansatz in der Therapie gastrointestinaler Tumoren dar. Bevacizumab (Avastin®), der erste zugelassene Angiogenese-Inhibitor, ist ein humanisierter monoklonaler Antikörper, der VEGF bindet und damit die Aktivierung des VEGF-Rezeptors verhindert. Ein weiteres antiangiogenes Wirkprinzip besteht in der pharmakologischen Hemmung des VEGF-Rezeptors im Bereich seiner Tyrosinkinase-Funktion. Einige dieser oral applizierbaren Angiogeneseinhibitoren werden bereits in großen Phase-III-Studien in der Erst- und Zweitlinientherapie geprüft, nachdem sie erfolgreich das Phase-I-Programm durchlaufen haben. Zusammenfassend konnte die Anti-Angiogenese als therapeutisches Konzept in der Tumortherapie validiert werden.

Abstract

Neovascularization is a prerequisite for progressive growth of solid tumors and their metastases. This highly complex process is tightly regulated by a large number of proangiogenic and antiangiogenic factors and by further interactions of the tumor with blood vessels and extracellular matrix. Recently, numerous proangiogenic factors had been identified and characterized as molecular targets for pharmacological inhibition. Most of these proangiogenic factors represent growth factors, which specifically interact with and thereby activating receptor tyrosine kinases. One of the most important regulators of angiogenesis is the vascular endothelial growth factor (VEGF). VEGF stimulates endothelial cell proliferation. Most antiangiogenic drugs directly interact with vascular endothelial cells or interfere with proangiogenic growth factors or its receptor tyrosine kinases. Especially the blockade of the VRGF/VEGF-receptor organization represents an important novel strategy in the treatment of gastrointestinal malignancies. Bevacizumab (Avastin^®) is a humanised monoclonal VEGF antibody preventing activation of the VEGF-receptor and has been recently approved for the first and second line treatment of colorectal cancer in combination with chemotherapy. Other drugs interact with the VEGF-receptor by inhibiting the receptor tyrosine kinase. A number of orally applicable inhibitors of the receptor tyrosine kinase are currently been tested in phase III trials. Taken together, these studies further validated antiangiogenesis as a promising therapeutic strategy in the treatment of cancer.

Schlüsselwörter

Angiogenese - Inhibitoren - gastroenterologische Tumoren - klinische Studien - Phase I-III - Biomarker

Key words

angiogenesis - inhibitors - gastrointestinal cancer - clinical studies - phase I-III - biomarker

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