Anti-CD33-antibodies labelled with the alpha-emitter Bismuth-213 kill CD33-positive acute myeloid leukaemia cells specifically by activation of caspases and break radio- and chemoresistance by inhibition of the anti-apoptotic proteins X-linked inhibitor of apoptosis protein and B-cell lymphoma-extra large.

Aim: The emerging interest in radioimmunotherapies employing alpha-emitters for cancer treatment like high risk-leukaemia leads to the question of how these radionuclides exhibit their cytotoxicity. To clarify the molecular mechanisms of cell death induction, we investigated the molecular effects of the alpha-emitter Bismuth-213 (Bi-213) bound to a monoclonal anti-CD33-antibody ([Bi-213]anti-CD33) on the cell cycle and on apoptosis induction in sensitive as well as in beta- and gamma-radiation-resistant CD33-positive acute myeloid leukaemia (AML) cells.

Methods: The cytotoxic potential of the radioimmunoconjugate [Bi-213]anti-CD33 was analysed in the CD33-expressing human AML cell line HL-60 and in radiation- and chemoresistant HL-60-derived cell lines.

Targeted alpha-therapy using [Bi-213]anti-CD20 as novel treatment option for radio- and chemoresistant non-Hodgkin lymphoma cells.

Radioimmunotherapy (RIT) is an emerging treatment option for non-Hodgkin lymphoma (NHL) producing higher overall response and complete remission rates compared with unlabelled antibodies. However, the majority of patients treated with conventional or myeloablative doses of radiolabelled antibodies relapse. The development of RIT with alpha-emitters is attractive for a variety of cancers because of the high linear energy transfer (LET) and short path length of alpha-radiation in human tissue, allowing higher tumour cell kill and lower toxicity to healthy tissues.