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High-dose multidrug resistance in primary human hematopoietic progenitor
cells transduced with optimized retroviral vectors
HG Eckert, M Stockschlader, U Just, S Hegewisch-Becker, M Grez, A Uhde, A Zander, W Ostertag and C Baum
Department of Cell and Virus Genetics, Heinrich-Pette-Institute for
Experimental Virology and Immunology, Hamburg University, Germany.
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
multidrug-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.
Volume 88,
Issue 9,
pp. 3407-3415,
11/01/1996
Copyright © 1996 by The American Society of Hematology
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