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Cytokine prestimulation as a gene therapy strategy: implications for using
the MDR1 gene as a dominant selectable marker
CA Blau, T Neff and T Papayannopoulou
Department of Medicine, University of Washington, Seattle 98195, USA.
A major obstacle to stem cell gene therapy is the extremely low efficiency
of stem cell transduction. In vivo selection is a strategy for enriching a
minor population of genetically modified bone marrow cells through the
introduction of a drug resistance gene, followed by subsequent
administration of the corresponding cytotoxic drug in vivo. Achieving
persistent effects from in vivo selection is expected to require selection
at the level of stem cells or, minimally, selection at the level of
progenitors. Major limitations to in vivo selection are the nonhematologic
toxicities of the cytotoxic drugs used and the resistance of stem cells and
progenitors to killing by most cytotoxic agents. Experiments were performed
in mice to evaluate whether the drugs used for selection in combination
with multiple drug resistance gene 1 (MDR1) could have an enhanced effect
on clonogenic progenitors if preceded by administration of the cytokine,
stem cell factor (SCF). Single doses of taxol, navelbine, or vinblastine
produced 10-fold reductions in the total number of mononuclear cells per
femur, indicating a significant depletion of nonclonogenic precursor cells.
However, for each of these agents, clonogenic progenitors, assayed as
colony-forming unit cells and day-12 spleen colony-forming units, were
relatively spared. Administration of SCF before taxol, navelbine, or
vinblastine completely abrogated the progenitor-sparing phenomenon, because
clonogenic progenitors were depleted as effectively as nonclonogenic
precursor cells. Furthermore, the administration of SCF before drug
administration allowed the dosages of taxol and vinblastine to be reduced
by more than half, while retaining reductions in progenitor numbers that
were unachievable using very high doses of the cytotoxic drug alone.
Doxorubicin administration resulted in a 30- to 40-fold depletion in
progenitors that was not significantly altered by preceding SCF
administration. These results suggest that previous observations of in vivo
selection using MDR1 gene transfer followed by taxol administration may
have resulted from selection at the level of relatively mature,
nonclonogenic precursor cells. Furthermore, these data suggest that
cytokine prestimulation may be a useful strategy for improving the
selection of drug-resistant clonogenic progenitors and, possibly, stem
cells in vivo.
Volume 89,
Issue 1,
pp. 146-154,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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