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¹²³I-ITdU–Mediated Nanoirradiation of DNA Efficiently Induces Cell Kill in HL60 Leukemia Cells and in Doxorubicin-, ß-, or -Radiation–Resistant Cell Lines

Nuclear Medicine Clinic, Universität Ulm, Ulm, Germany

Correspondence: For correspondence or reprints contact: Sven N. Reske, MD, Universität Ulm, Klinik für Nuklearmedizin, Robert-Koch-Strasse 8, D-89081 Ulm, Germany. E-mail: sven.reske{at}uniklinik-ulm.de

Resistance to radiotherapy or chemotherapy is a common cause of treatment failure in high-risk leukemias. We evaluated whether selective nanoirradiation of DNA with Auger electrons emitted by 5-¹²³I-iodo-4'-thio-2'-deoxyuridine (¹²³I-ITdU) can induce cell kill and break resistance to doxorubicin, ß-, and -irradiation in leukemia cells. Methods: 4'-thio-2'-deoxyuridine was radiolabeled with ^123/131I and purified by high-performance liquid chromatography. Cellular uptake, metabolic stability, DNA incorporation of ¹²³I-ITdU, and the effect of the thymidylate synthase (TS) inhibitor 5-fluoro-2'-deoxyuridine (FdUrd) were determined in HL60 leukemia cells. DNA damage was assessed with the comet assay and quantified by the olive tail moment. Apoptosis induction and irradiation-induced apoptosis inhibition by benzoylcarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.fmk) were analyzed in leukemia cells using flow cytometry analysis. Results: The radiochemical purity of ITdU was 95%. Specific activities were 900 GBq/µmol for ¹²³I-ITdU and 200 GBq/µmol for ¹³¹I-ITdU. An in vitro cell metabolism study of ¹²³I-ITdU with wild-type HL60 cells demonstrated an uptake of 1.5% of the initial activity/10⁶ cells of ¹²³I-ITdU. Ninety percent of absorbed activity from ¹²³I-ITdU in HL60 cells was specifically incorporated into DNA. ¹²³I-ITdU caused extensive DNA damage (olive tail moment > 12) and induced more than 90% apoptosis in wild-type HL60 cells. The broad-spectrum inhibitor of caspases zVAD-fmk reduced ¹²³I-ITdU–induced apoptosis from more than 90% to less than 10%, demonstrating that caspases were central for ¹²³I-ITdU–induced cell death. Inhibition of TS with FdUrd increased DNA uptake of ¹²³I-ITdU 18-fold and the efficiency of cell kill about 20-fold. In addition, ¹²³I-ITdU induced comparable apoptotic cell death (>90%) in sensitive parental leukemia cells and in leukemia cells resistant to ß-irradiation, -irradiation, or doxorubicin at activities of 1.2, 4.1, 12.4, and 41.3 MBq/mL after 72 h. This finding indicates that ¹²³I-ITdU breaks resistance to ß-irradiation, -irradiation, and doxorubicin in leukemia cells. Conclusion: ¹²³I-ITdU–mediated nanoirradiation of DNA efficiently induced apoptosis in sensitive and resistant leukemia cells against doxorubicin, ß-irradiation, and -irradiation and may provide a novel treatment strategy for overcoming resistance to conventional radiotherapy or chemotherapy in leukemia. Cellular uptake and cell kill are highly amplified by inhibiting TS with FdUrd.

Key Words: Auger radiation • nuclear targeting • treatment • DNA nanoirradiation • chemoresistance • radioresistance

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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