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

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-x(L), 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.

• Authors: Claudia Friesen, Annelie Lubatschofski, Jörg Kotzerke, Inga Buchmann, Sven N Reske, Klaus-Michael Debatin
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 30 Issue 9 Pg. 1251-61 (Sep 2003) ISSN: 1619-7070 [Print] Germany
• PMID: 12830326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Comment)

Chemical References

• fas Receptor
• Caspases

Topics

• Apoptosis (radiation effects)
• Beta Particles
• Caspases (metabolism)
• Cell Line, Tumor (metabolism, radiation effects)
• Dose-Response Relationship, Radiation
• Enzyme Activation (radiation effects)
• Gamma Rays
• HL-60 Cells
• Humans
• Leukemia-Lymphoma, Adult T-Cell (metabolism)
• Mitochondria (metabolism, radiation effects)
• Radiation Dosage
• Radiation Tolerance
• Radioimmunotherapy (methods)
• Radiometry (methods)
• fas Receptor (metabolism)