Differences between in vivo and in vitro sensitivity to imatinib of Bcr/Abl+ cells obtained from leukemic patients
| Autor: | Carlo Gambacorti-Passerini, Holger Ruchatz, Silvia Bungaro, Roberta Frapolli, Gianmarco Corneo, Magda Verga, Pietro Pioltelli, Lucia Tornaghi, Francesca Rossi, Massimo Zucchetti, Leonardo Scapozza, Maurizio D'Incalci, Fabio Rossi, Enrico Maria Pogliani, Rosalind H. Gunby |
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| Rok vydání: | 2002 |
| Předmět: |
Fusion Proteins
bcr-abl Apoptosis Pharmacology Piperazines chemistry.chemical_compound In vivo Recurrence hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive medicine Humans Kinase activity Phosphorylation neoplasms Molecular Biology ABL Blood Cells Chemistry breakpoint cluster region Myeloid leukemia Imatinib Tyrosine phosphorylation Cell Biology Hematology Imatinib mesylate Pyrimidines Drug Resistance Neoplasm Benzamides Cancer research Imatinib Mesylate Molecular Medicine Blast Crisis Cell Division medicine.drug |
| Zdroj: | Blood cells, moleculesdiseases. 28(3) |
| ISSN: | 1079-9796 |
| Popis: | Imatinib mesylate (imatinib) inhibits Bcr/Abl, an oncogenic fusion protein. The in vitro effects of imatinib on BCR/ABL+ leukemic cells include inhibition of Bcr/Abl tyrosine phosphorylation, block of proliferation, and induction of apoptosis. The in vivo effects of imatinib were evaluated in 12 CML (chronic myeloid leukemia) patients in blast crisis or accelerated phase who were treated with imatinib. Treatment caused a decrease in spontaneous proliferation of leukemic cells in 10 of 12 evaluable patients and the development of apoptosis in 9 of 11 cases. Imatinib also caused an inhibition of Bcr/Abl autophosphorylation; however, the degree of inhibition obtained in vivo was substantially lower than that achieved in vitro with similar concentrations of imatinib. In seven patients cells could be evaluated at relapse: spontaneous proliferation was no longer inhibited and Bcr/Abl phosphorylation was comparable or superior to that present at the beginning of treatment, before imatinib administration. Plasma imatinib concentrations were not reduced. Leukemic cells obtained at relapse maintained in vitro sensitivity (Bcr/Abl autophosphorylation and proliferation inhibition) to imatinib concentration measured in vivo (3 microM or higher), although a partial resistance to the antiproliferative effects of imatinib was present at low (0.01-0.3 microM) concentrations. In four patients, addition of erythromycin to blood samples obtained at relapse restored imatinib sensitivity in terms of phosphorylation inhibition, indicating that the majority of plasma imatinib was not available to cells and probably bound to alpha1 acid glycoprotein. These data suggest that measurements of Bcr/Abl kinase activity in peripheral blood samples may represent a more reliable indicator of active concentrations than the measurement of imatinib plasma levels. |
| Databáze: | OpenAIRE |
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