PMID- 12783379
OWN - NLM
STAT- MEDLINE
DCOM- 20040304
LR  - 20151119
IS  - 0037-1963 (Print)
IS  - 0037-1963 (Linking)
VI  - 40
IP  - 2 Suppl 2
DP  - 2003 Apr
TI  - Cytogenetic and molecular mechanisms of resistance to imatinib.
PG  - 69-79
AB  - Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (Gleevec) 
      (formerly STI571) is a promising new therapeutic strategy in patients with 
      chronic myelogenous leukemia (CML). Despite significant hematologic and 
      cytogenetic responses, resistance occurs in patients with chronic phase (CP) and 
      advanced disease. A cohort of 72 patients with CML in myeloid blast crisis (BC) 
      (n = 34), lymphoid BC (n = 2), accelerated phase (AP) (n = 16), CP (n = 18), and 
      BCR-ABL(+) acute lymphoblastic leukemia (ALL) (n = 2) resistant to imatinib were 
      investigated. Median levels of BCR-ABL transcripts, determined by quantitative 
      reverse-transcriptase polymerase chain reaction (RT-PCR), were not significantly 
      changed at the time of resistance, but seven of 55 patients showed a greater than 
      10-fold increase in BCR-ABL levels. Genomic amplification of BCR-ABL was found in 
      two of 32 patients evaluated by fluorescence in situ hybridization (FISH). 
      Additional chromosomal aberrations were observed in 19 of 36 patients and point 
      mutations of the ABL tyrosine kinase domain resulting in reactivation of the 
      BCR-ABL tyrosine kinase were detected in 29 of 72 patients. Resistance may be 
      caused by BCR-ABL-independent or BCR-ABL-dependent mechanisms. A thorough 
      evaluation of resistant cases is required to suggest therapeutic measures in the 
      individual case. Clonal selection of resistant cells harboring a BCR-ABL mutation 
      might be reversed by stopping imatinib therapy and switching to chemotherapy. 
      Combination therapy from the start of treatment to reduce the frequency of 
      resistance is currently being evaluated with several drugs.
CI  - Copyright 2003 Elsevier Inc. All rights reserved.
FAU - Hochhaus, Andreas
AU  - Hochhaus A
AD  - III Medizinische Universitatsklinik, Fakultat fur Klinische Medizin Mannheim der 
      Universitat Heidelberg, Mannheim, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Semin Hematol
JT  - Seminars in hematology
JID - 0404514
RN  - 0 (Benzamides)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - 0 (RNA, Neoplasm)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.10.2 (Fusion Proteins, bcr-abl)
SB  - IM
MH  - Benzamides
MH  - Chromosome Aberrations
MH  - Clone Cells/pathology
MH  - Cytogenetic Analysis
MH  - DNA Mutational Analysis
MH  - Disease Progression
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Fusion Proteins, bcr-abl/genetics
MH  - Genes, abl/genetics
MH  - Humans
MH  - Imatinib Mesylate
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/genetics/pathology
MH  - Piperazines/pharmacology/*therapeutic use
MH  - Point Mutation
MH  - Pyrimidines/pharmacology/*therapeutic use
MH  - RNA, Neoplasm/analysis
MH  - Treatment Outcome
EDAT- 2003/06/05 05:00
MHDA- 2004/03/05 05:00
CRDT- 2003/06/05 05:00
PHST- 2003/06/05 05:00 [pubmed]
PHST- 2004/03/05 05:00 [medline]
PHST- 2003/06/05 05:00 [entrez]
AID - S0037196303000787 [pii]
AID - 10.1053/shem.2003.50045 [doi]
PST - ppublish
SO  - Semin Hematol. 2003 Apr;40(2 Suppl 2):69-79. doi: 10.1053/shem.2003.50045.