Transfer of the MDR1 gene into haematopoietic cells

The multidrug resistance gene MDR1 encodes a cell-membrane protein, Pgp, which acts as an energy-dependent pump able to extrude many compounds out of cells . Pgp expression in a wide variety of human cancers results in pleiotropic resistance to anticancer drugs including anthracyclines, mitoxantrone, vinca alkaloids, epipodophyllotoxins, actinomycin D, and paclitaxel. In normal tissues, Pgp is expressed on the lumenal surface of epithelial cells of the liver, kidney, small and large intestines, and pancreatic ductules, in the adrenal cortex and steroid secreting glands of the endometrium, and on endothelial cells in testis and brain. Its presence in these locations suggests that this transporter contributes to the excretion of xenobiotics or toxic endogenous substrates, to steroid secretion, and as a component of the blood-brain barrier. Pgp is also expressed at low to moderate levels in haematopoietic cells and its potential role in the protection of stem cells from toxic insults and as a transporter of cytokines, cytotoxic effector molecules, or inflammatory mediators in leucocytes has been discussed. Whether this low normal MDR1 expression results in an intrinsic multidrug resistance of Pgp-expressing haematopoietic cells remains unclear. However, clinical myelosuppressive side-effects of chemotherapeutic agents, including Pgp-expelled cytotoxic drugs, clearly limits dose-intensification in the treatment of solid tumours. Transfer of the MDR1 gene into haematopoietic cells has been achieved in vitro and in vivo in animal models, resulting in protection from cytotoxic Pgp substrates in MDR1-expressing cells. This suggests the potential use of MDR1 to protect the bone marrow of patients undergoing high-dose chemotherapy for solid tumours. Moreover, efficient gene therapy of genetic diseases of the haematopoietic system is limited by the low proportion of successfully transduced or transfected cells and the usual impossibility of selecting the targeted cells based on transgene expression. MDR1 may allow selection of haematopoietic cells co-expressing an otherwise non-selectable transgene. In this review, the pattern of Pgp expression in normal bone marrow (BM) and peripheral blood (PB) haematopoietic cells, and in vitro and in vivo transfer experiments of the human MDR1 gene into haematopoietic cells will be reviewed. Finally, the potential use and limitations of MDR1 in gene therapy will be discussed.