PT  - JOURNAL ARTICLE
AU  - Sven Reske
AU  - Sandra Deisenhofer
AU  - Gerhard Glatting
AU  - Boris Zlatopolskiy
AU  - Andreas Vogg
AU  - Claudia Friesen
TI  - Auger-electron-DNA-targeted therapy breaks chemo- and radioresistance in leukemia cells
DP  - 2007 May 01
TA  - Journal of Nuclear Medicine
PG  - 346P--346P
VI  - 48
IP  - supplement 2
4099  - http://jnm.snmjournals.org/content/48/supplement_2/346P.2.short
4100  - http://jnm.snmjournals.org/content/48/supplement_2/346P.2.full
SO  - J Nucl Med2007 May 01; 48
AB  - 1497 Objectives: Chemo- and radioresistance are considered one of the primary reasons for therapeutic failure in leukemias and solid tumors. DNA is the principal target for the biological effect of ionizing radiation. Auger-electrons-emitter such as I-123 with low energy and short range target DNA within a few nm with limited side effects. Radiolabelled thymidine analogs would be a promising approach to target the DNA through incorporation into DNA. In this study we analyzed the molecular requirements for radiolabelled thymidine analogs induced cell killing in sensitive, chemo- and radioresistant leukemia cells. Methods: Sensitive, chemo- and radioresistant CEM and HL-60 leukemia cells were incubated with different activities (41.3-0.0041 MBq/ml) of I-123 or [I-123]-5-I-4’-thio-2’-deoxyuridine ([I-123]ITdU). 0.5, 1, 2 and 24h after irradiation cell uptake and DNA incorporation was measured. 24, 48, 72h after irradiation cell death, apoptosis and cell cycle were analyzed using FACS analysis. Activation of apoptosis pathways was performed using Western blot analysis and DNA damage was measured using Comet-assay. Results: [I-123]ITdU was efficiently taken up and incorporated into DNA in HL-60 cells. A strong induction of cell death were found in sensitive and in beta-radiation-, gamma-radiation- and doxorubicin-resistant leukemia cells treated with [I-123]-ITdU. Cells treated with non-labelled I-123 or with non radioactive [I-127]-ITdU survived, suggesting that Auger-electron-emitters selectively induced cell death via DNA incorporation. [I-123]-ITdU-induced cell death was completely caspase dependent. [I-123]ITdU activated caspase-3 and -8 and cleaved PARP in leukemia cells. [I-123]ITdU-mediated mitochondria damage resulted in caspase-9 activation. In contrast to gamma- and beta-irradiation, upregulation of CD95 ligand and CD95 receptor were not detected. In addition, after treatment with [I-123]-ITdU we found a cell cycle arrest in G(2)/M phase and a upregulation of p21. Furthermore, repair of [I-123]ITdU induced DNA damage was severely impaired. Conclusions: Auger-electon-DNA-targeted therapy with radiolabelled thymidine analogs activates apoptosis pathways and seems to be a promising therapeutic approach for selectively killing tumor cells with limited side effects and for breaking chemo- and radioresistance.