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Titolo:
Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance
Autore:
Mahon, FX; Deininger, MWN; Schultheis, B; Chabrol, J; Reiffers, J; Goldman, JM; Melo, JV;
Indirizzi:
Hammersmith Hosp, Imperial Coll, Sch Sci Technol & Med, Dept Haematol, London W12 0NN, England Hammersmith Hosp London England W12 0NN aematol, London W12 0NN, England Univ Victor Segalen, Lab Greffe de Moelle, Bordeaux, France Univ Victor Segalen Bordeaux France Greffe de Moelle, Bordeaux, France
Titolo Testata:
BLOOD
fascicolo: 3, volume: 96, anno: 2000,
pagine: 1070 - 1079
SICI:
0006-4971(20000801)96:3<1070:SACOBP>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; MULTIDRUG-RESISTANCE; PHILADELPHIA-CHROMOSOME; P-GLYCOPROTEIN; HEMATOLOGICAL MALIGNANCIES; CLINICAL-SIGNIFICANCE; FUSION PROTEINS; MESSENGER-RNA; IN-VIVO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Melo, JV Hammersmith Hosp, Imperial Coll, Sch Sci Technol & Med, Dept Haematol, Ducane rd, London W12 0NN, England Hammersmith Hosp Ducane rd LondonEngland W12 0NN 2 0NN, England
Citazione:
F.X. Mahon et al., "Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance", BLOOD, 96(3), 2000, pp. 1070-1079

Abstract

Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an attractive therapeutic strategy in chronic myelogenous leukemia (CML), A few CML cell lines and primary progenitors are, however, resistant to this compound, We investigated the mechanism of this resistance in clones of the murine BaF/3 cells transfected with BCR-ABL and in 4 human cell lines from which sensitive (s) and resistant (r) clones were generated by various methods. Although the resistant cells were able to survive in the presence of STI571, their proliferation was approximately 30% lower than that of their sensitive counterparts in the absence of the compound. The concentration of STI571 needed for a 50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 mu mol/L) than in the sensitive(0.2-0.25 mu mol/L) clones. The mechanism of resistance to STI571 varied among the cell lines, Thus, in Baf/BCR-ABL-r, LAMA84-r, and AR230-r, there was up-regulation of the Bcr-Abl protein associated with amplification of the BCR-ABL gene, In K562-r, there was no Bcr-Abl overexpression, but the IC50 for the inhibition of Bcr-Abl autophosphorylation was increased in the resistant clones. Sequencing of the Abl kinase domain revealed no mutations. The multidrug resistance P-glycoprotein (Pgp) was overexpressed in LAMA84-r, indicating that at least 2 mechanisms of resistance operate in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a higher threshold for tyrosine kinase inhibition by STI571, We conclude that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR-ABL. (C) 2000 by The American Society of Hematology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 20:52:18