Breaking chemoresistance and radioresistance with [213Bi]anti-CD45 antibodies in leukemia cells.
Cancer Res
; 67(5): 1950-8, 2007 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-17332322
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 alpha-particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the alpha-emitter (213)Bi ([(213)Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks beta-irradiation-, gamma-irradiation-, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to beta-irradiation-, gamma-irradiation-, and doxorubicin-mediated apoptosis and DNA damage, [(213)Bi]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, [(213)Bi]anti-CD45 activated apoptosis pathways in leukemia cells through the mitochondrial pathway but independent of CD95 receptor/CD95 ligand interaction. Furthermore, [(213)Bi]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 [(213)Bi]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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tolerância a Radiação
/
Radioisótopos
/
Bismuto
/
Leucemia
/
Radioimunoterapia
/
Antígenos Comuns de Leucócito
/
Resistencia a Medicamentos Antineoplásicos
Tipo de estudo:
Evaluation_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article