TY - JOUR
T1 - In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age
T2 - a report of the Dutch and German Leukemia Study Groups
AU - Dutch and German Leukemia Study Groups
AU - Ramakers-van Woerden, N L
AU - Pieters, R
AU - Hoelzer, D
AU - Slater, R M
AU - den Boer, M L
AU - Loonen, A H
AU - Harbott, J
AU - Janka-Schaub, G E
AU - Ludwig, W-D
AU - Ossenkoppele, G J
AU - van Wering, E R
AU - Veerman, A J P
N1 - Copyright 2002 Wiley-Liss, Inc.
PY - 2002/6
Y1 - 2002/6
N2 - BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL).PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases.RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients.CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.
AB - BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL).PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases.RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients.CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.
KW - ATP Binding Cassette Transporter, Subfamily B, Member 1/analysis
KW - Adult
KW - Antineoplastic Agents/therapeutic use
KW - Child
KW - Drug Resistance, Neoplasm/genetics
KW - Drug Screening Assays, Antitumor
KW - Humans
KW - Immunophenotyping
KW - In Vitro Techniques
KW - Leukocyte Count
KW - Multidrug Resistance-Associated Proteins/analysis
KW - Neoplasm Proteins/analysis
KW - Philadelphia Chromosome
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Prednisolone/therapeutic use
KW - Prognosis
KW - Vault Ribonucleoprotein Particles/genetics
U2 - 10.1002/mpo.10087
DO - 10.1002/mpo.10087
M3 - Article
C2 - 11984797
SN - 0098-1532
VL - 38
SP - 379
EP - 386
JO - Medical and pediatric oncology
JF - Medical and pediatric oncology
IS - 6
ER -