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Blood, 15 December 2003, Vol. 102, No. 13, pp. 4541-4546.
Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2002-11-3612.
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NEOPLASIA
Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia
Amy Holleman,
Monique L. den Boer,
Karin M. Kazemier,
Gritta E. Janka-Schaub, and
Rob Pieters
From the Department of Paediatric Oncology/Haematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands; and the Cooperative Acute Lymphoblastic Leukemia (COALL) study group, Hamburg, Germany.
Resistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the 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) externalization and mitochondrial transmembrane (  m) depolarization followed by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) inactivation in the majority of patients. For all 4 drugs, a significant inverse correlation was found between cellular drug resistance and (1) the percentage of cells with PS externalization (< .001 < P < .008) and (2) the percentage of cells with m depolarization (.002 < P < .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 = .001; P = .001) and L-asparaginase (P = .01; P = .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 externalization and m depolarization. This leads to decreased activation of apoptotic parameters in resistant cases of pediatric ALL. (Blood. 2003;102:4541-4546)
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