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Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2002-11-3612.
Submitted December 2, 2002
Accepted August 10, 2003
Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukaemia
Amy Holleman*, Monique L den Boer, Karin M Kazemier, Gritta E Janka-Schaub, and Rob Pieters
Department of Paediatric Oncology/Haematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
COALL Study Group, Hamburg, Germany
* Corresponding author; email: a.holleman{at}erasmusmc.nl.
Resistance of leukaemic cells to chemotherapeutic agents is associated with an unfavourable outcome in paediatric ALL. To investigate underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in leukemic cells from 50 children with ALL was studied after in vitro exposure with 4 important drugs in ALL therapy (prednisolone, vincristine, L-asparaginase and daunorubicin). Exposure to each drug resulted in early induction of phosphatidylserine (PS) externalisation and mitochondrial transmembrane (  m) depolarisation followed by caspase-3 activation and PARP inactivation in the majority of patients. For all four drugs, a significant inverse correlation was found between cellular drug resistance and (1) the percentage of cells with PS externalisation (<0.001<P<0.008) and (2) the percentage of cells with m depolarisation (0.002<P<0.02). However, the percentage of cells with caspase-3 activation and the percentage of cells with PARP inactivation showed a significant inverse correlation with cellular resistance for prednisolone (P=0.001; P=0.001) and L-asparaginase (P=0.01; P=0.001) only. This suggests that caspase-3 activation and PARP inactivation are not essential for vincristine and daunorubicin-induced apoptosis. In conclusion, resistance to 4 unrelated drugs is associated with defect(s) upstream or at the level of PS externalisation and m depolarisation. This leads to decreased activation of apoptotic parameters in resistant cases of paediatric ALL.
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