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Radiat Res. 2008 Mar;169(3):301-10. doi: 10.1667/RR1067.1.

MDR1 gene transfer using a lentiviral SIN vector confers radioprotection to human CD34+ hematopoietic progenitor cells.

Author information

1
Department of Radiation Oncology, Mannheim Medical Centre, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. patrick.maier@radonk.ma.uni-heidelberg.de

Abstract

Tumor radiotherapy with large-field irradiation results in an increase in apoptosis of the radiosensitive hematopoietic stem cells (CD34(+)). The aim of this study was to demonstrate the radioprotective potential of MDR1 overexpression in human CD34(+) cells using a lentiviral self-inactivating vector. Transduced human undifferentiated CD34(+) cells were irradiated with 0-8 Gy and held in liquid culture under myeloid-specific maturation conditions. After 12 days, MDR1 expression was determined by the rhodamine efflux assay. The proportion of MDR1-positive cells in cells from four human donors increased with increasing radiation dose (up to a 14-fold increase at 8 Gy). Determination of expression of myeloid-specific surface marker proteins revealed that myeloid differentiation was not affected by transduction and MDR1 overexpression. Irradiation after myeloid differentiation also led to an increase of MDR1-positive cells with escalating radiation doses (e.g. 12.5-16% from 0-8 Gy). Most importantly, fractionated irradiation (3 x 2 Gy; 24-h intervals) of MDR1-transduced CD34(+) cells resulted in an increase in MDR1-positive cells (e.g. 3-8% from 0-3 x 2 Gy). Our results clearly support a radioprotective effect of lentiviral MDR1 overexpression in human CD34(+) cells. Thus enhancing repopulation by surviving stem cells may increase the radiation tolerance of the hematopoietic system, which will contribute to widening the therapeutic index in radiotherapy.

PMID:
18302483
DOI:
10.1667/RR1067.1
[Indexed for MEDLINE]

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