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Breaking Chemoresistance and Radioresistance with [²¹³Bi]anti-CD45 Antibodies in Leukemia Cells

¹ Nuclear Medicine Clinic, ² Department of Transfusion Medicine, and ³ University Children's Hospital, University of Ulm, Ulm, Germany and ⁴ European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany

Requests for reprints: Claudia Friesen, Nuclear Medicine Clinic, University of Ulm, Robert-Koch-Straße 8, D-89081 Ulm, Germany. Phone: 49-731-500-61342; Fax: 49-731-500-61302; E-mail: claudia.friesen{at}uni-ulm.de.

Chemoresistance and radioresistance are considered one of the primary reasons for therapeutic failure in leukemias and solid tumors. Targeted radiotherapy using monoclonal antibodies radiolabeled with -particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the -emitter ²¹³Bi ([²¹³Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks ß-irradiation–, -irradiation–, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to ß-irradiation–, -irradiation–, and doxorubicin-mediated apoptosis and DNA damage, [²¹³Bi]anti-CD45–induced DNA damage was not repaired, and apoptosis was not inhibited by the nonhomologous end-joining DNA repair mechanism. Depending on the activation of caspase-3, caspase-8, and caspase-9, [²¹³Bi]anti-CD45 activated apoptosis pathways in leukemia cells through the mitochondrial pathway but independent of CD95 receptor/CD95 ligand interaction. Furthermore, [²¹³Bi]anti-CD45 reversed deficient activation of caspase-3, caspase-8, and caspase-9, deficient cleavage of poly(ADP-ribose) polymerase, and deficient activation of mitochondria in chemoresistant and in radioresistant and apoptosis-resistant leukemia cells. These findings show that [²¹³Bi]anti-CD45 is a promising therapeutic agent to break chemoresistance and radioresistance by overcoming DNA repair mechanisms in leukemia cells and provide the foundation for discovery of novel anticancer compounds. [Cancer Res 2007;67(5):1950–8]

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