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  • resistance  (2)
  • 1
    Keywords: CELLS ; tumor ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; THERAPY ; FOLLOW-UP ; QUANTIFICATION ; LONG-TERM ; GENE ; gene therapy ; TIME ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; TRANSPLANTATION ; BIOLOGY ; BREAST-CANCER ; NO ; resistance ; VECTOR ; IMMUNODEFICIENT MICE ; STEM-CELLS ; PROGENITOR CELLS ; POLYMERASE-CHAIN-REACTION ; CHAIN-REACTION ; HEMATOPOIETIC-CELLS ; PERIPHERAL-BLOOD ; MULTIDRUG-RESISTANCE ; RESISTANCE MDR-1 GENE ; retroviral vector ; insertional mutagenesis ; LACKING ; multidrug resistance ; CHAIN ; ONCOLOGY ; THERAPIES ; polymerase chain reaction ; P-GLYCOPROTEIN ; BONE-MARROW-CELLS ; stem cells ; LEVEL ; USA ; progenitor cell ; microbiology ; STEM ; PROGENITOR-CELL ; rhesus macaque ; biotechnology ; CD34+ ; DOMINANCE ; long-term follow-up ; multidrug resistance 1
    Abstract: Previous murine studies have suggested that retroviral multidrug resistance 1 ( MDR1) gene transfer may be associated with a myeloproliferative disorder. Analyses at a clonal level and prolonged long-term follow-up in a model with more direct relevance to human biology were lacking. In this study, we analyzed the contribution of individual CD34selected peripheral blood progenitor cells to long-term rhesus macaque hematopoiesis after transduction with a retroviral vector either expressing the multidrug resistance 1 gene ( HaMDR1 vector) or expressing the neomycin resistance ( NeoR) gene ( G1Na vector). We found a total of 122 contributing clones from 8 weeks up to 4 years after transplantation. One hundred two clones contained the G1Na vector, whereas only 20 clones contained the HaMDR1 vector. Here, we show for the first time realtime polymerase chain reaction based quantification of individual transduced cell clones constituting 0.0008% +/- 0.0003% to 0.0041% +/- 0.00032% of primate peripheral blood cells. No clonal dominance was observed
    Type of Publication: Journal article published
    PubMed ID: 17615269
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  • 2
    Keywords: CANCER ; IN-VITRO ; KINASE ; TYROSINE KINASE ; DISEASE ; resistance ; MUTATIONS ; INTERFERON-ALPHA ; CHRONIC MYELOGENOUS LEUKEMIA ; ORGANIZATION ; IMATINIB MESYLATE ; COMBINATION THERAPY ; CML ; COMPLETE MOLECULAR REMISSION ; DISCONTINUATION ; mathematical modelling
    Abstract: BACKGROUND: Newly diagnosed patients with chronic myeloid leukaemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib or dasatinib. However, incomplete eradication of residual disease is a general problem of long-term TKI therapy. Activation of mouse haematopoietic stem cells by interferon-alpha (IFN alpha) stimulated the discussion of whether a combination treatment leads to accelerated eradication of the CML clone. METHODS: We base our simulation approach on a mathematical model describing human CML as a competition phenomenon between normal and malignant cells. We amend this model to incorporate the description of IFN alpha activity and simulate different scenarios for potential treatment combinations. RESULTS: We demonstrate that the overall sensitivity of CML stem cells to IFN alpha activation is a crucial determinant for the benefit of a potential combination therapy. We furthermore show that pulsed IFN alpha together with continuous TKI administration is the most promising strategy for a combination treatment in which the therapeutic benefit prevails adverse side effects. CONCLUSION: Our modelling approach is a highly beneficial tool to quantitatively address the competition between normal and leukaemic haematopoiesis in treated CML patients. We derive testable predictions for different experimental settings that are suggested before the clinical implementation of the combination treatment.
    Type of Publication: Journal article published
    PubMed ID: 22538973
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