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  • 1
    Keywords: EXPRESSION ; IN-VIVO ; THERAPY ; TYROSINE KINASE ; GENE ; TRANSDUCTION ; resistance ; CHRONIC MYELOID-LEUKEMIA ; AAV ; VIRUS VECTORS ; IMATINIB STI571
    Abstract: Gene transfer into chronic myelogenous leukemia (CML) cells may become of relevance for overcoming therapy resistance. Single-stranded pseudotyped adeno-associated viruses of serotypes 2/1 to 2/6 (ssAAV2/1--ssAAV2/6) were screened on human CML cell lines and primary cells to determine gene transfer efficiency. Additionally, double-stranded self-complementary vectors (dsAAVs) were used to determine possible second-strand synthesis limitations. On human CML cell lines, ssAAV2/2 and ssAAV2/6 were most efficient. On primary cells, ssAAV2/6 proved significantly more efficient (4.1 aEuroS +/-+/- aEuroS2.5%% GFP〈SU++〈/SU cells, p aEuroS== aEuroS0.011) than the other vectors (〈 1%%). The transduction efficiency could be significantly increased (45.5 aEuroS +/-+/- aEuroS13.4%%) by using dsAAV2/6 vectors (p aEuroS 〈 aEuroS0.001 vs. ssAAV2/6). In these settings, our data suggest conversion of single- to double-stranded DNA and cell binding/entry as rate-limiting steps. Furthermore, gene transfer was observed in both late and earlier CML (progenitor) populations. For the first time, efficient AAV gene transfer into human CML cells could be shown, with the potential for future clinical application.
    Type of Publication: Journal article published
    PubMed ID: 21323526
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  • 2
    Keywords: APOPTOSIS ; CELLS ; IN-VITRO ; INHIBITOR ; COMBINATION ; Germany ; INHIBITION ; THERAPY ; TYROSINE KINASE ; PROTEIN ; LINES ; MECHANISM ; mechanisms ; CELL-LINES ; resistance ; LINE ; OVEREXPRESSION ; CHRONIC MYELOGENOUS LEUKEMIA ; CHRONIC MYELOID-LEUKEMIA ; imatinib ; drug resistance ; DRUG-RESISTANCE ; cell lines ; MESYLATE ; P-GLYCOPROTEIN ; CHEMOTHERAPEUTIC DRUGS ; PLUS ; MDR1 ; BCR-ABL ; PHILADELPHIA-CHROMOSOME ; PGP ; 17-AAG ; CHROMOSOME-POSITIVE LEUKEMIA ; CLINICAL RESISTANCE ; STI571 ; synergism
    Abstract: Overexpression of BCR-ABL and P-glycoprotein (Pgp) are two of the known mechanisms of imatinib resistance. As combination therapy may allow to overcome drug resistance, we investigated the effect of combination treatment with imatinib and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heat-shock protein 90 (Hsp90) inhibitor, on different imatinib-Sensitive and imatinib-resistant CML cell lines. In imatinib-sensitive cells, combination index (CI) values obtained using the method of Chou and Talalay indicated additive ( CI 1) or marginally antagonistic (CI 〉 1) effects following simultaneous treatment with imatinib and 17-AAG. In imatinib-resistant cells both drugs acted synergistically (CI 〈 1). In primary chronic-phase CML cells additive or synergistic effects of the combination of imatinib plus 17-AAG were discernible. Annexin V/propidium iodide staining showed that the activity of imatinib plus 17-AAG is mediated by apoptosis. Combination treatment with imatinib plus 17-AAG was more effective in reducing the BCR-ABL protein level than 17-AAG alone. Monotherapy with 17-AAG decreased P-glycoprotein activity, which may increase intracellular imatinib levels and contribute to the sensitization of CML cells to imatinib. The results suggest that combination of imatinib and 17-AAG may be useful to overcome imatinib resistance in a clinical setting
    Type of Publication: Journal article published
    PubMed ID: 15902298
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  • 3
    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; BLOOD ; CELL ; Germany ; KINASE ; PATHWAY ; TYROSINE KINASE ; RNA ; transcription ; cell line ; LINES ; PATIENT ; MECHANISM ; FLOW ; CELL-LINES ; TYROSINE KINASE INHIBITOR ; MOLECULE ; bone marrow ; BONE-MARROW ; leukemia ; LINE ; TRAFFICKING ; ADHESION ; CELL-ADHESION ; PROGENITOR CELLS ; POLYMERASE-CHAIN-REACTION ; ADHESION MOLECULE ; CD34(+) CELLS ; CHRONIC MYELOGENOUS LEUKEMIA ; chronic myelogenous leukemia,adhesion molecule,L-selectin,imatinib mesylate ; CHRONIC MYELOID-LEUKEMIA ; CYTOGENETIC RESPONSES ; FLOW-CYTOMETRY ; HEMATOPOIETIC PROGENITOR CELLS ; HEMATOPOIETIC-CELLS ; imatinib ; INTERFERON-ALPHA RESTORES ; L-SELECTIN EXPRESSION ; MARROW STROMA ; PERIPHERAL-BLOOD
    Abstract: Chronic myelogenous leukemia (CML) is characterized by aberrant trafficking of malignant hematopoietic progenitor cells in the peripheral blood. Expression of the cell adhesion molecule CD62L was reported to be significantly lower in CML patients than in normal controls. We studied whether the transcription of CD62L in CML cells is dependent on the activity of the BCR-ABL tyrosine kinase. Following addition of the Abelson (ABL) tyrosine kinase inhibitor imatinib (formerly STI571) to two BCR-ABL-positive cell lines (BV173, SD-1), we observed a dose-dependent increase in CD62L RNA levels of up to 45-fold by a quantitative, real-time polymerase chain reaction and an increase in the amount of cell surface-bound CD62L of up to 18-fold by quantitative flow cytometry, respectively. These data are validated by an increased CD62L expression in the bone marrow of patients (n=6) with advanced CML who received imatinib. Restoration of defective cell adhesion mediated via the CD62L pathway may be one mechanism of action of imatinib in BCR-ABL-positive leukemias
    Type of Publication: Journal article published
    PubMed ID: 12714574
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  • 4
    Keywords: APOPTOSIS ; CELLS ; GROWTH ; AGENTS ; Germany ; INHIBITION ; THERAPY ; TYROSINE KINASE ; DEATH ; LINES ; PATIENT ; CELL-LINES ; treatment ; STAGE ; ASSAY ; resistance ; CELL-DEATH ; CELL-LINE ; leukemia ; LINE ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; CHRONIC MYELOGENOUS LEUKEMIA ; CHRONIC MYELOID-LEUKEMIA ; imatinib ; cell lines ; HEMATOLOGIC MALIGNANCIES ; INHIBITORS ; P-GLYCOPROTEIN ; ASSAYS ; PHASE ; BCR-ABL ; CML ; PHILADELPHIA-CHROMOSOME ; RESISTANT ; MONOTHERAPY ; FARNESYL TRANSFERASE INHIBITOR ; farnesyltransferase inhibitor ; L744,832 ; LB42918 ; LOW-DOSE CYTARABINE ; RAS SIGNALING PATHWAY
    Abstract: Background: Resistance to imatinib monotherapy frequently emerges in advanced stages of chronic myelogenous leukemia (CML), supporting the rationale for combination drug therapy. In the present study, the activities of the farnesyltransferase inhibitors (FTIs) L744,832 and LB42918, as single agents and in combination with imatinib, were investigated in different imatinib-sensitive and -resistant BCR-ABL-positive CML cells. Materials and Methods: Growth inhibition of the cell lines and primary patient cells was assessed by MTT assays and colony-forming cell assays, respectively. Drug interactions were analyzed according to the median-effect method of Chou and Talalay. The determination of apoptotic cell death was performed by annexin V/propidium iodide staining. Results: Combinations of both FTIs with imatinib displayed synergism or sensitization (potentiation) in all the cell lines tested. In primary chronic phase CML cells, additive and synergistic effects were discernible for the combination of imatinib plus L744,832 and imatinib plus LB42918, respectively. Annexin V/propidium iodide staining showed enhancement of imatinib-induced apoptosis with either drug combination, both in imatinib-sensitive and -resistant cells. Conclusion: The results indicated the potential of L744,832 and LB42918 as combination agents for CML patients on imatinib treatment
    Type of Publication: Journal article published
    PubMed ID: 16827161
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