Zusammenfassung
Niedermolekulare synthetische Moleküle (small molecules) haben in jüngster Zeit erhebliches Interesse für die Behandlung solider Tumoren gefunden. Sie richten sich vorwiegend gegen Rezeptoren der Signaltransduktion (Tyrosinkinasen, EGF), die für die Proliferation bei manchen Subtypen maligner Tumoren von entscheidender Bedeutung sind. Während die EGF-Rezeptorblockade hinsichtlich der dadurch gebotenen therapeutischen Optionen noch schwer abschätzbar ist, hat die Blockade von c-kit, einem homologen Stammzellfaktor bei der CML und bei gastrointestinalen Stromatumoren, bereits einen festen Stellenwert erreicht. Die Beeinflussung von PDGF-, von VEGF- oder anderen Rezeptoren beruht meist auf der Blockade der kristallografisch ermittelten Struktur der Kinasedomäne mit Behinderung der Phosphorylierung. Das Medikamenten-Engineering ist hierbei von entscheidender Bedeutung, aber auch die Subklassifikation von Malignomen, um tatsächlich denjenigen Tumortyp zur Behandlung zu bringen, bei dem der blockierbare Rezeptor einen oder den entscheidenden Schritt der Tumorproliferation darstellt. Hierfür sind Genexpressionsstudien auf der Basis von Mikroarrays eine wichtige Voraussetzung. Da unklar ist, wie lange eine Rezeptorblockade anhält, sollte bei Resektabilität des Residualtumors der operative Eingriff angestrebt werden. Zu berücksichtigen ist, dass für Operationen unter den Bedingungen der Rezeptorblockade noch wenige Erfahrungen vorliegen. Die Aufklärung der Resistenzmechanismen gegenüber small molecules hat für die CML und GIST gerade begonnen und verspricht wichtige Aufschlüsse über intratumorale Anpassungsvorgänge an medikamentöse Rezeptorblockaden zu liefern.
Abstract
Small molecules represent a group of orally taken inhibitors of signaling cascades that have gained increasing attention for the treatment of solid tumors. EGF and VEGF as well as c-kit receptors are targets to stop proliferation in certain subtypes of cancer known to depend mainly on these pathways for progression. The efficacy of targeting the EGF receptor has still to be proven for colorectal cancer, NSCLC, and tumors of the head and neck. However, targeting c-kit protooncogene in chronic myeloid leukemia and GI stromal tumors (GIST) with imatinib has become standard. To target the receptors mentioned or PDGF depends on successful drug engineering based on knowledge about conformation of relevant kinase domains. Consecutively, phosphorylation of the receptor is blocked. Gene expression studies on the basis of microarrays represent the other side of the coin to select the relevant subgroup of malignancies for treatment in which the receptor to be blocked is really the clue to proliferation. At the present stage of knowledge, it remains often unclear how long the time period of tumor control via small molecule administration might be. Therefore, if resectability of the residual tumor has been confirmed, surgery should be strongly considered. As there is still little experience in this setting, unexpected morbidity might occur. Clarification of the mechanisms of resistance to small molecules has already begun for CML and GIST and promises to provide important information for a better understanding of the mechanisms of tumor growth.
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Hohenberger, P. Therapie mit „small molecules“. Onkologe 10, 38–45 (2004). https://doi.org/10.1007/s00761-003-0637-4
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DOI: https://doi.org/10.1007/s00761-003-0637-4