Zusammenfassung
Die Hemmung der Tyrosinkinasen durch intrazellulär wirksame kleine Moleküle ist ein innovatives Therapieprinzip bei der Behandlung maligner Erkrankungen. Imatinib, ein Inhibitor der bcr-abl-Tyrosinkinase, ist Therapiestandard bei der CML und ebenso bei der Behandlung von Phi+-ALL, GIST und der Eosinophilen-Leukämie wirksam. Neue Tyrosinkinaseinhibitoren wie Dasatinib oder Nilotinib können durch andere Bindungseigenschaften bei imatinibresistenter CML Anwendung finden. Multityrosinkinaseinhibitoren wie z. B. Sunitinib und Sorafenib zeigen unter anderem Wirksamkeit beim Nierenzellkarzinom. Durch Erlotinib und Gefitinib ist beim nichtkleinzelligen Bronchialkarzinom eine signifikante Verlängerung des Überlebens möglich. Auch für das metastasierte Pankreaskarzinom zeigt Erlotinib in der Kombination mit Gemcitabin einen Überlebensvorteil. Lapatinib kann in Kombination mit Capecitabin eine Trastuzumab-Resistenz bei HER2-positivem Mammakarzinom überwinden.
Thalidomid und Lenalidomid entfalten ihre Wirkung als immunomodulatorische Medikamente (IMiDs) über verschiedene Mechanismen. Sowohl in der Mono- als auch in der Kombinationstherapie sind sehr gute Remissionsraten und ein verbessertes Gesamtüberleben beim multiplen Myelom erreichbar. Bei Patienten mit einem myelodysplastischen 5q-Syndrom konnte Lenalidomid langfristige Remissionen mit Erreichen einer Transfusionsunabhängigkeit induzieren. Ein komplett neues Therapieprinzip ist die Inhibition des Proteasoms. Die Induktion der Apoptose von Lymphom- und Myelomzelllinien ist auch auf die klinische Anwendung übertragbar und zeigt sehr gute Ansprechraten sowohl in der Mono- als auch in der Kombinationstherapie bei ansonsten refraktärem multiplem Myelom.
Für die beschriebenen neuen Therapieprinzipien, die sog. „targeted therapy“, zeigt sich in der klinischen Anwendung ein Nebenwirkungsspektrum, das sich von den herkömmlicher Zytostatika unterscheidet.
Abstract
Intracellular inhibition of tyrosine kinases with small molecules is an innovative therapeutic principal for malignant diseases. Inhibition of the bcr-abl tyrosine kinase with imatinib is the therapeutic standard for chronic myeloid leukaemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Phi+-ALL). Because imatinib inhibits c-kit and the platelet-derived growth factor (PDGF) receptor as well, it also has a therapeutic potential in gastrointestinal stromal tumors (GIST) or hypereosinophilic syndrome. Newer tyrosine kinases like dasatinib and nilotinib can overcome imatinib resistance in CML. The spectrum of diseases for multityrosine kinase inhibitors includes renal cell carcinoma, which is sensitive to sunitinib and sorafenib. Erlotinib and gefitinib prolong the survival for patients with non-small cell lung cancer in second and third line therapy. In combination with gemcitabine, erlotinib achieves a low survival benefit. Lapatinib is able to overcome trastuzumab resistant HER2 positive breast cancer in combination with capecitabine.
Thalidomide and the immunomodulatory drug lenalidomide show different mechanisms of action. For multiple myeloma, prolonged overall survival can be achieved with single agent or combination therapy. In patients with myelodysplastic 5q syndrome, lenalidomide induces long-term remission and independence with respect to transfusions. Inhibition of the proteasome with bortezomib is another novel therapeutic principal, to be used essentially in multiple myeloma with good remission rates in cases of refractory disease.
The new methods involving targeted therapies are accompanied by a different spectrum of adverse reactions than those found with conventional chemotherapy.
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Es besteht kein Interessenkonflikt bei PD Dr. F. Weissinger. Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen. Die Präsentation des Themas ist unabhängig und die Darstellung der Inhalte produktneutral.
Herr Dr. D. Fabbro ist Mitarbeiter von Novartis Pharma.
Herr Prof. H. Einsele gibt Vortragstätigkeiten für Ortho Biotec und Calgem an.
Trotz des möglichen Interessenkonflikts ist der Beitrag unabhängig und produktneutral.
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Die Autoren F. Weissinger und D. Fabbro sind gleichberechtigte Erstautoren.
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Weissinger, F., Fabbro, D. & Einsele, H. Signalübermittlungsinhibitoren. Onkologe 13, 213–226 (2007). https://doi.org/10.1007/s00761-006-1169-5
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DOI: https://doi.org/10.1007/s00761-006-1169-5