Holleman Amy, den Boer Monique L, Kazemier Karin M, Janka-Schaub Gritta E, Pieters Rob
Erasmus MC/Sophia Children's Hospital, Pediatric Oncology/Hematology, Rm Sp2456, Dr Molewaterplein 60, PO Box 2060, 3000 CB Rotterdam, The Netherlands.
Blood. 2003 Dec 15;102(13):4541-6. doi: 10.1182/blood-2002-11-3612. Epub 2003 Aug 14.
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 (Deltapsim) 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 Deltapsim 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 Deltapsim depolarization. This leads to decreased activation of apoptotic parameters in resistant cases of pediatric ALL.
白血病细胞对化疗药物的耐药性与儿童急性淋巴细胞白血病（ALL）的不良预后相关。为了研究细胞耐药的潜在机制，我们对50例ALL患儿白血病细胞在体外暴露于ALL治疗中的4种重要药物（泼尼松龙、长春新碱、L-天冬酰胺酶和柔红霉素）后，各种凋亡参数的激活情况进行了研究。暴露于每种药物后，大多数患者早期诱导了磷脂酰丝氨酸（PS）外化和线粒体跨膜电位（Δψm）去极化，随后是半胱天冬酶-3激活和聚（ADP-核糖）聚合酶（PARP）失活。对于所有4种药物，在细胞耐药性与（1）PS外化细胞百分比（<.001 < P <.008）和（2）Δψm去极化细胞百分比（.002 < P <.02）之间发现了显著的负相关。然而，半胱天冬酶-3激活细胞百分比和PARP失活细胞百分比仅与泼尼松龙（P =.001；P =.001）和L-天冬酰胺酶（P =.01；P =.001）的细胞耐药性呈显著负相关。这表明半胱天冬酶-3激活和PARP失活对于长春新碱和柔红霉素诱导凋亡并非必不可少。总之，对4种不相关药物的耐药性与PS外化和Δψm去极化上游或该水平的缺陷相关。这导致儿童ALL耐药病例中凋亡参数的激活减少。
