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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 1950-1956
Granulocyte Colony-Stimulating Factor Enhances Bone Marrow Stem Cell
Damage Caused by Repeated Administration of Cytotoxic Agents
Ronald van Os,
Simon Robinson,
Tara Sheridan,
John M.K. Mislow,
Donald Dawes, and
Peter M. Mauch
From the Joint Center for Radiation Therapy, Department of Radiation
Oncology, Harvard Medical School, Boston, MA.
Despite the increasing use of cytokines to circumvent the acute
dose-limiting myelotoxicity of cancer treatment, little is known about
the combined effects of cytotoxic agents and cytokines on the primitive
stem cells responsible for long-term hematopoiesis. In an experimental
model, we administered cytotoxic agents that have variable effects on
primitive stem cells in C57BL/6 (B6)-mice. Mice received six
every-other-week doses of cyclophosphamide (CY, 84 mg/kg),
VP-16 (24 mg/kg) + cisplatinum (2.4 mg/kg),
carboplatinum (50 mg/kg), chlorambucil (12 mg/kg), BCNU
(13.2 mg/kg), or TBI (80 cGy). Granulocyte
colony-stimulating factor (G-CSF; 250 µg/kg/day) was administered
subcutaneously twice daily on days 3 to 6 after each dose of the
cytotoxic agent. Comparison with animals receiving the cytotoxic agent
alone was made to investigate the effects of G-CSF on long-term
hematopoiesis. Hematopoiesis was measured 20 weeks after the last dose
of the cytotoxic agent by assessment of peripheral blood counts, marrow
cellularity, progenitor cell content (colony-forming units-spleen;
CFU-S), and primitive stem cell number (long-term repopulating ability
and day 28 and day 35 cobblestone area-forming cell [CAFC]
frequencies). Exposure to cytotoxic agents alone resulted in a
significant decrease in primitive stem cells (as measured by
repopulating units [RU] and day 28 and day 35 CAFC content) in
animals given carboplatinum, chlorambucil, BCNU, and TBI, but not in
animals treated with cyclophosphamide or VP-16 and cisplatinum. The
addition of G-CSF resulted in a significant decrease in stem cell
content when compared with no G-CSF administration in animals treated
with chlorambucil, BCNU, or TBI. Thus, G-CSF administered after
repeated exposure to cytotoxic agents, appeared to damage the primitive
stem cell compartment when used in combination with agents known to
damage primitive stem cells. These results, although obtained in an
experimental model, should raise concerns for the indiscriminate use of
G-CSF in the clinic.
© 1998 by The American Society of Hematology.
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