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|Title:||Breaking Chemo- and Radioresistance with [Bi-213]anti-CD45 Antibodies in Leukemia Cells|
|Authors:||FRIESEN C.; GLATTING G.; KOOP B.; SCHWARZ K.; MORGENSTERN ALFRED; APOSTOLIDIS CHRISTOS; DEBATIN K.m.; RESKE S.n.|
|Citation:||CANCER RESEARCH vol. 67 no. 5 p. 1950-1958|
|Publisher:||AMER ASSOC CANCER RESEARCH|
|Type:||Articles in Journals|
|Abstract:||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 A-particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the A-emitter 213Bi ([213Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks B-irradiation–, ;-irradiation–, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to B-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 endjoining 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.|
|JRC Institute:||Institute for Transuranium Elements|
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