In:
Blood, American Society of Hematology, Vol. 102, No. 13 ( 2003-12-15), p. 4541-4546
Abstract:
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 (Δψm) 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 ( & lt; .001 & lt; P & lt; .008) and (2) the percentage of cells with Δψm depolarization (.002 & lt; P & lt; .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 Δψm depolarization. This leads to decreased activation of apoptotic parameters in resistant cases of pediatric ALL. (Blood. 2003;102:4541-4546)
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2002-11-3612
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2003
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
