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In vivo synergy between recombinant human stem cell factor and recombinant
human granulocyte colony-stimulating factor in baboons enhanced circulation
of progenitor cells
RG Andrews, RA Briddell, GH Knitter, T Opie, M Bronsden, D Myerson, FR Appelbaum and IK McNiece
Clinical Research Division, Fred Hutchinson Cancer Research Center,
Seattle, WA 98104.
Recombinant human stem cell factor (rhSCF) and recombinant human
granulocyte colony-stimulating factor (rhG-CSF) are synergistic in vitro in
stimulating the proliferation of hematopoietic progenitor cells and their
precursors. We examined the in vivo synergy of rhSCF with rhG-CSF for
stimulating hematopoiesis in vivo in baboons. Administration of low-dose
(LD) rhSCF (25 micrograms/kg) alone did not stimulate changes in
circulating WBCs. In comparison, administration of LD rhSCF in combination
with rhG-CSF at 10 micrograms/kg or 100 micrograms/kg stimulated increases
in circulating WBCs of multiple types up to twofold higher than was
stimulated by administration of the same dose of rhG-CSF alone. When the
dose of rhG-CSF is increased to 250 micrograms/kg, the administration of LD
rhSCF does not further increase the circulating WBC counts. Administration
of LD rhSCF in combination with rhG-CSF also stimulated increased
circulation of hematopoietic progenitors. LD rhSCF alone stimulated less of
an increase in circulating progenitors, per milliliter of blood, than did
administration of rhG-CSF alone at 100 micrograms/kg. Baboons administered
LD rhSCF together with rhG-CSF at 10, 100, or 250 micrograms/kg had 3.5- to
16-fold higher numbers per milliliter of blood of progenitors cells of
multiple types, including colony-forming units granulocyte/macrophage
(CFU-GM), burst-forming unit-erythroid (BFU-E), and colony-forming and
burst-forming units-megakaryocyte (CFU- MK and BFU-MK) compared with
animals given the same dose of rhG-CSF without rhSCF, regardless of the
rhG-CSF dose. The increased circulation of progenitor cells stimulated by
the combination of rhSCF plus rhG-CSF was not necessarily directly related
to the increase in WBCs, as this effect on peripheral blood progenitors was
observed even at an rhG-CSF dose of 250 micrograms/kg, where
coadministration of LD rhSCF did not further increase WBC counts.
Administration of very-low- dose rhSCF (2.5 micrograms/kg) with rhG-CSF, 10
micrograms/kg, did not stimulate increases in circulating WBCs, but did
increase the number of megakaryocyte progenitor cells in blood compared
with rhG-CSF alone. LD rhSCF administered alone for 7 days before rhG-CSF
did not result in increased levels of circulating WBCs or progenitors
compared with rhG- CSF alone. Thus, the synergistic effects of rhSCF with
rhG-CSF were both dose- and time-dependent. The doses of rhSCF used in
these studies have been tolerated in vivo in humans.(ABSTRACT TRUNCATED AT
400 WORDS)
Volume 84,
Issue 3,
pp. 800-810,
08/01/1994
Copyright © 1994 by The American Society of Hematology
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