Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells

  • Claudia Friesen
  • Annelie Lubatschofski
  • Jörg Kotzerke
  • Inga Buchmann
  • Sven N. Reske
  • Klaus-Michael Debatin
Original Article

DOI: 10.1007/s00259-003-1216-z

Cite this article as:
Friesen, C., Lubatschofski, A., Kotzerke, J. et al. Eur J Nucl Med Mol Imaging (2003) 30: 1251. doi:10.1007/s00259-003-1216-z

Abstract

Beta-irradiation used for systemic radioimmunotherapy (RIT) is a promising treatment approach for high-risk leukaemia and lymphoma. In bone marrow-selective radioimmunotherapy, beta-irradiation is applied using iodine-131, yttrium-90 or rhenium-188 labelled radioimmunoconjugates. However, the mechanisms by which beta-irradiation induces cell death are not understood at the molecular level. Here, we report that beta-irradiation induced apoptosis and activated apoptosis pathways in leukaemia cells depending on doses, time points and dose rates. After beta-irradiation, upregulation of CD95 ligand and CD95 receptor was detected and activation of caspases resulting in apoptosis was found. These effects were completely blocked by the broad-range caspase inhibitor zVAD-fmk. In addition, irradiation-mediated mitochondrial damage resulted in perturbation of mitochondrial membrane potential, caspase-9 activation and cytochrome c release. Bax, a death-promoting protein, was upregulated and Bcl-xL, a death-inhibiting protein, was downregulated. We also found higher apoptosis rates and earlier activation of apoptosis pathways after gamma-irradiation in comparison to beta-irradiation at the same dose rate. Furthermore, irradiation-resistant cells were cross-resistant to CD95 and CD95-resistant cells were cross-resistant to irradiation, indicating that CD95 and irradiation used, at least in part, identical effector pathways. These findings demonstrate that beta-irradiation induces apoptosis and activates apoptosis pathways in leukaemia cells using both mitochondrial and death receptor pathways. Understanding the timing, sequence and molecular pathways of beta-irradiation-mediated apoptosis may allow rational adjustment of chemo- and radiotherapeutic strategies.

Keywords

RadioimmunotherapyBeta-irradiationApoptosisLeukaemiaRhenium-188

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Claudia Friesen
    • 1
  • Annelie Lubatschofski
    • 1
  • Jörg Kotzerke
    • 2
  • Inga Buchmann
    • 2
  • Sven N. Reske
    • 2
  • Klaus-Michael Debatin
    • 1
  1. 1.University Children's HospitalUlmGermany
  2. 2.Department of Nuclear MedicineUniversity of UlmUlmGermany