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• W4236305864 abstract "Radiation-induced apoptosis has only minor influence on clonogenic survival of tumor cells from most solid tumors. However, normal hematopoietic cells are particularly sensitive to ionising radiation with apoptosis as a major inactivation pathway. Overexpression of the multidrug resistance 1 (MDR1) gene product, P-glycoprotein (P-gp), leads to suppression of apoptosis. Therefore, gene therapy with MDR1 might provide protection of the bone marrow/normal tissue cells during radiotherapy. The aim of this study was to test the feasibility of this approach by demonstrating that human CD34+ blood stem cells can be protected from the effect of radiation by MDR1 gene transduction. We further tested the mechanism to suppress radiation induced apoptosis by MDR1 gene transduction of human lymphoblastoid cell lines with different p53 status and apoptosis susceptibility. As a tumor model we used a human ovarian cancer cell line. CD34+ cells were isolated from three individual donors. After pre-stimulation, cells were exposed to retroviral supernatant containing the hybrid vector SF1m carrying the MDR1 gene. After retroviral transduction, 1x105 cells of transduced and non-transduced CD34+ control cells, respectively, were irradiated with 0–6 Gy and held in liquid culture under differentiation conditions. Ten days after irradiation, cell counts were performed and MDR-1 gene expression was determined by their ability to efflux Rhodamine-(Rh-)123. Secondly, human lymphoblastoid cell lines TK6, TK6E6, WTK1 retrovirally transduced with the MDR1 gene, the human ovarian cancer cell line A2780 and P-gp-overexpressing A2780/M250 were irradiated. Apoptosis was measured using the Nicoletti sub-G1 assay and clonogenic survival was determined by colony formation. Ten days after irradiation of CD34+ cells, the total number of cells was significantly higher (3-10-fold) in MDR1-transduced compared to non-transduced cultures. At the clinical relevant fraction size, D = 2 Gy for non-transduced controls, the mean dose-modifying factor for transduction with MDR1 was 0.54 (range: 0.49–0.62). The Rh-123 data showed that 12.3 ± 3.6% (mean ± std.dev.) of the cells in the transduced cultures were Rh-123 negative (i.e. expressed P-gp) independently of the radiation dose whereas only 1% of non-transduced cells were Rh-123 negative. In the human lymphoblastoid cell lines TK6, TK6E6, WTK1 and in the human ovarian cancer cell line A2780/M250, P-gp overexpression suppressed radiation-induced apoptosis. However, for the tumor cells, this was not accompanied by an increase of clonogenic radioresistance. For the p53 wild-typ TK6 cells the MDR-1 gene transfer increases also the clonogenic radioresistance, similar to the effects of PMA or caspase inhibition. The more radioresistant TK6E6 cells (p53 neg.) were less affected by P-gp expression, and no change in survival was recorded for the WTK1 cells (p53 mutated). Inhibition of P-gp with Cyclosporin A restored vincristine toxicity in A2780/M250 cells but had no effect on suppression of radiation-induced apoptosis, indicating that P-gp may act through different pathways. The results demonstrate that efficient radio-protection of human blood stem cells by MDR1 gene transduction is feasible. Thus, enhancing repopulation by surviving stem cells may increase the tolerance of hematopoietic cells and thus contribute to widening the therapeutic range in radiotherapy" @default.
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• W4236305864 date "2004-09-01" @default.
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• W4236305864 title "Radioprotection of human CD34+ blood stem cells transduced with the multidrug resistance 1 (MDR1) gene" @default.
• W4236305864 doi "https://doi.org/10.1016/s0360-3016(04)01489-0" @default.
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