Zielgerichtete Radionuklidtherapie mit α-Emittern - Grundlagen, experimentelle und erste klinische Studien

Zusammenfassung

α-Partikel-emittierende Nuklide besitzen hohes zytotoxisches Potenzial und eignen sich daher für die zielgerichtete Radionuklidtherapie von Tumorerkrankungen. Aufgrund ihres hohen linearen Energietransfers (LET) verbunden mit einer kurzen Reichweite im Gewebe verursachen α-Partikel schwerwiegende DNA-Schäden, die nur fehlerhaft repariert werden und schließlich zum Tod der Zellen führen. Für die zielgerichtete Therapie werden α-Emitter, wie Actinium-225, Astat-211, Wismut-213 und Thorium-227 mittels geeigneter Chelatoren an Antikörper oder Rezeptorliganden gekoppelt, die spezifisch an Proteine binden, die auf Tumorzellen vermehrt oder exklusiv exprimiert werden. Viel versprechend erscheint die Applikation von α-Emittern vor allem in der zielgerichteten Therapie von disseminierten Tumorzellen oder kleinen Tumorzellclustern, die nach Resektion von Primärtumoren im Körper verbleiben. α-Emitter-Konjugate wurden in einer Reihe experimenteller Studien, wie zum Beispiel zur Therapie des Ovarial-, Kolon-, Magen- und Mammakarzinoms erfolgreich eingesetzt. Erste klinische Studien mit α-Emitter-Antikörper-Konjugaten zur Verträglichkeit und therapeutischen Effizienz beim Melanom, beim Ovarialkarzinom, bei der akuten myeloischen Leukämie (AML) sowie bei Gliomen zeigen ebenfalls positive Ergebnisse. Das Ziel könnte daher die klinische Etablierung der zielgerichteten α-Emitter-Radionuklidtherapie sein, als ein Bestandteil eines multimodalen Therapiekonzeptes für Tumorerkrankungen.

Abstract

α-particle emitting nuclides are highly cytotoxic and are thus promising candidates for use in targeted radionuclide therapy of cancer. Due to their high linear energy transfer (LET) combined with a short range in tissue, α-particles cause severe DNA-damages that are repaired inaccurately and finally trigger cell death. For targeted therapy, α-emitters like actinium-225, astatine-211, bismuth-213 and thorium-227 are coupled to antibodies or receptor ligands via appropriate chelators that bind to proteins that are overexpressed or exclusively expressed on tumour cells. Application of α-emitters seems particularly promising for targeted therapy of disseminated tumour cells and small tumour cell clusters that remain in the body following resection of the primary tumour. α-emitter conjugates have been successfully applied in numerous experimental studies for therapy of ovarian, colon, gastric and breast cancer. Initial clinical trials evaluating α-emitter antibody conjugates in terms of tolerance and therapeutic efficacy also have shown positive results in patients with melanoma, ovarian cancer, acute myeloid lymphoma (AML) and glioma. Therefore the aim could be clinical establishment of targeted α-emitter radionuclide therapy as one part of a multimodal concept for therapy of cancer.

Schlüsselwörter

α-Emitter - zielgerichtete Radionuklidtherapie - minimal residuale Erkrankung - lokoregionale Applikation - relative biologische Wirksamkeit (RBW) - Radiopeptidkonjugate - Radioimmunkonjugate

Key words

α-emitter - targeted radionuclide therapy - minimal residual disease - locoregional application - relative biological effectiveness (RBE) - radiopeptideconjugates - radioimmunoconjugates

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