gms | German Medical Science

27th German Cancer Congress Berlin 2006

German Cancer Society (Frankfurt/M.)

22. - 26.03.2006, Berlin

Article

Send article

Radioimmunotherapy with Y-90 labelled anti-CD45 monoclonal antibodies induces DNA-damage and activates apoptosis pathways in vivo

Meeting Abstract

Search Medline for

  • corresponding author presenting/speaker Claudia Friesen - Abteilung Nuklearmedizin, Ulm, Deutschland
  • Klaus-Michael Debatin - Abteilung Kinder- und Jugendmedizin, Ulm
  • Donald Bunjes - Abteilung Hämatologie/Onkologie, Ulm
  • Sven N. Reske - Abteilung Nuklearmedizin, Ulm

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO118

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dkk2006/06dkk228.shtml

Published: March 20, 2006

© 2006 Friesen et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

Text

Aim: Targeted radiotherapy of bone marrow with radiolabelled monoclonal antibodies is a therapeutic approach of considerable potential for the treatment of relapsing leukemias for escalating conditioning prior to stem cell transplantation. Beta-irradiation induces apoptosis and activates apoptosis pathway involving the CD95 receptor/CD95 ligand system in leukemia cells in vitro. However, the mechanisms by which beta-irradiation induces cell death during RIT in vivo are not well understood at the molecular level.

Methods: Peripheral blood lymphocytes (PBLs) were isolated from patients treated with 5 GBq of Y-90 labelled anti-CD45 monoclonal antibodies ([Y-90]anti-CD45). After 2, 4, 8, and 24 h induction of DNA damage in PBLs was assessed using Comet-assay and activation of apoptosis pathways in PBLs was performed using Western blot analysis.

Results: [Y-90]anti-CD45 induces DNA-damage, activates caspases, increases pro-apoptotic proteins and downregulates anti-apoptotic proteins in peripheral blood lymphocytes (PBLs) during RIT. Upregulation of death-inducing ligands (DIL) and receptors (DIL-R) such as CD95 were found in PBLs isolated from patients during RIT with [Y-90]anti-CD45 after 2 h. In addition, activation of caspases-8 and caspase-3 and PARP cleavage were detected in isolated PBLs during RIT after 2 h. In addition, we found that caspase-9 was activated, indicating that activation of mitochondria were involved during RIT with [Y-90]anti-CD45. Bax and Bcl-xS, death-promoting proteins, were upregulated and Bcl-xL, a death-inhibiting protein, was downregulated. Furthermore, we found a strong upregulation of p21, which was involved in cell cycle arrest.

Conclusions: It is shown that [Y-90]anti-CD45 induces DNA-damage, p21-mediated cell cycle arrest and activates extrinsic and intrinsic apoptosis pathways in PBLs. Targeted radiotherapy of bone marrow with radiolabelled monoclonal antibodies is a therapeutic approach of considerable potential for the treatment of relapsing leukemias for escalating conditioning prior to stem cell transplantation. Upregulation of CD95 ligand/receptor system will sensitize leukemic cells to cytotoxic effects of additional anticancer treatment.