Fluorodeoxyuridine mediated cell cycle synchronization in S-phase increases the Auger radiation cell killing with ¹²⁵I-iododeoxyuridine

Summary

Aim: ¹²⁵I-iododeoxyuridine is a potential Auger radiation therapy agent. Its incorporation in DNA of proliferating cells is enhanced by fluorodeoxyuridine. Here, we evaluated therapeutic activities of ¹²⁵I-iododeoxyuridine in an optimized fluorodeoxyuridine pre-treatment inducing S-phase synchronization. Methods: After S-phase synchronization by fluorodeoxyuridine, cells were treated with ¹²⁵I-iododeoxyuridine. Apoptosis analysis and S-phase synchronization were studied by flow cytometry. Cell survival was determined by colony-forming assay. Based on measured growth parameters, the number of decays per cell that induced killing was extrapolated. Results: Treatment experiments showed that 72 to 91% of synchronized cells were killed after 0.8 and 8 kBq/ml ¹²⁵I-iododeoxyuridine incubation, respectively. In controls, only 8 to 38% of cells were killed by corresponding ¹²⁵I-iododeoxyuridine activities alone and even increasing the activity to 80 kBq/ml gave only 42 % killing. Duplicated treatment cycles or repeated fluorodeoxyuridine pre-treatment allowed enhancing cell killing to >95 % at 8 kBq/ml ¹²⁵I-iododeoxyuridine. About 50 and 160 decays per S-phase cells in controls and S-phase synchronization, respectively, were responsible for the observed cell killing at 0.8 kBq/ml radio-iododeoxyuridine. Conclusion: These data show the successful application of fluorodeoxyuridine that provided increased ¹²⁵I-iododeoxyuridine Auger radiation cell killing efficacy through S-phase synchronization and high DNA incorporation of radio-iododeoxyuridine.

Zusammenfassung

Ziel: ¹²⁵I-Ioddeoxyuridin ist ein potenzielles Auger-Strahlentherapeutikum, dessen Einbau in die DNA sich teilender Zellen durch Fluorde-oxyuridin (FdUrd) erhöht wird. Wir untersuchten therapeutische Konzentrationen von ¹²⁵I-Ioddeoxyuridin innerhalb eines optimalen Therapieschemas von FdUrd-induzierter S-Phasen-Synchronisierung von Glioblastomzellen. Material, Methoden: Apoptose und Zellphasen wurden mittels Flusszytometrie gemessen. Die Zellüberlebensrate wurde anhand des Kolonie-Wachstumstests ermittelt. Wir haben ebenfalls unter Therapie in parallelen Experimenten die Daten ermittelt, die uns erlaubten, die Anzahl von ¹²⁵I-Zerfällen zu bestimmen, welche die Zellen abtöteten. Ergebnisse: Zwischen 72 und 91% der mit FdUrd synchronisierten Zellen wurden durch 0,8 und 8 kBq/ml ¹²⁵I-Ioddeoxyuridin abgetötet. Nur gerade 8 bis 38% der Kontrollzellen wurden durch ¹²⁵I-Ioddeoxyuridin allein zerstört und selbst Erhöhung auf 80 kBq/ml erhöhte die zytostatische Effizienz nur unwesentlich. Verdopplung der Behandlungszyklen oder Wiederholung der FdUrd-Vorbehandlung ergab eine erhöhte Zytotoxizität auf mehr als 95% bei 8 kBq ¹²⁵I-Ioddeoxyuridin. Bei 0.8 kBq/ml Radio-Ioddeoxyuridin bewirkten ungefähr 50 radioaktive Auger-Zerfälle den therapeutischen Effekt in Kontrollzellen und 160 Auger-Zerfälle denjenigen in S-Phasen-synchronisierten Zellen, gut vereinbar mit publizierten Toxizitätswerten von DNA-eingebauten Auger-Zerfällen. Schlussfolgerung: Die Resultate zeigen die erfolgreiche Anwendung von FdUrd, das die ¹²⁵I-Ioddeoxyuridin-Auger-Strahleneffizienz deutlich verstärkt, vermittelt durch S-Phasen-Synchronisierung und einen gesteigerten DNA-Einbau des Radio-Iod-deoxyuridins.

Keywords

Auger radiation treatment - ¹²⁵I-iododeoxy-uridine - fluorodeoxyuridine - cell cycle synchronization - glioblastoma

Schlüsselwörter

Auger-Strahlentherapie - ¹²⁵I-Iododeoxyuridin - Fluordeoxyuridin - Zellzyklus-Synchronisierung - Glioblastomzellen

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