High-Dose Multidrug Resistance in Primary Human Hematopoietic Progenitor Cells Transduced With Optimized Retroviral Vectors

Retroviral transfer of the multidrug-resistance 1 (mdr1) cDNA into primary human hematopoietic progenitor cells (HPC) of cancer patients undergoing high-dose chemotherapy has been proposed to protect the bone marrow from the dose-limiting cytotoxicity of cytostatic agents. Preclinical studies perfor...

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Bibliographic Details
Published in:Blood 1996-11, Vol.88 (9), p.3407-3415
Main Authors: Eckert, Hans-Georg, Stockschläder, Marcus, Just, Ursula, Hegewisch-Becker, Susanna, Grez, Manuel, Uhde, Almut, Zander, Axel, Ostertag, Wolfram, Baum, Christopher
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Cells, Cultured
Drug Resistance, Multiple - genetics
Gene Transfer Techniques
General aspects
Genes, MDR
Genetic Vectors
Hematopoietic Stem Cells - metabolism
Humans
Leukemia Virus, Murine
Medical sciences
Mice
Pharmacology. Drug treatments
Sarcoma Viruses, Murine
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Summary:Retroviral transfer of the multidrug-resistance 1 (mdr1) cDNA into primary human hematopoietic progenitor cells (HPC) of cancer patients undergoing high-dose chemotherapy has been proposed to protect the bone marrow from the dose-limiting cytotoxicity of cytostatic agents. Preclinical studies performed with vectors derived from the Moloney murine leukemia virus (MoMuLV) or the related Harvey murine sarcoma virus have established that chemoprotection of HPC is feasible. The efficacy of vector-mediated multi-drug-resistance under high doses of cytostatic agents, however, remained unclear. We report here that this goal can only be achieved with improved vector design. Novel vectors termed SF-MDR and MP-MDR, which are based on the spleen focus-forming virus or the myeloproliferative sarcoma virus for the enhancer and the murine embryonic stem cell virus for the leader, significantly elevate survival of transduced primary human HPC under moderate doses of colchicine and paclitaxel in vitro when compared with a conventional MoMuLV-based vector. Importantly, SF-MDR and also MP-MDR confer an absolute advantage at high doses of paclitaxel in vitro corresponding to peak plasma levels achieved in patients during chemotherapy. This observation has important consequences for a variety of ongoing and planned gene therapy trials.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V88.9.3407.bloodjournal8893407