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Prophylactic pretreatment of mice with hematopoietic growth factors induces
expansion of primitive cell compartments and results in protection against
5-fluorouracil-induced toxicity
G de Haan, B Donte, C Engel, M Loeffler and W Nijhof
Groningen Institute for Drug Studies, Department of Hematology, University
of Groningen, Groningen, The Netherlands.
The aim of this study was to expand the primitive and committed
hematopoietic cell compartments in vivo in order to confer resistance of
the blood cell forming system against the cytotoxic, cell cycle specific
drug 5-fluorouracil (5-FU). Possible chemoprotective effects of such a
pretreatment could result from increased numbers of hematopoietic cells,
present before 5-FU administration. In addition, we hypothesized that an
enhanced number of primitive and progenitor calls would result in a reduced
cycling activity, ie, 5-FU sensitivity, of these same cells, due to normal
physiological feedback loops. Administration of stem cell factor (SCF) plus
interleukin-11 (IL-11) to mice was shown to result in expansion of the
various immature cell compartments in marrow and, in particular, spleen.
The total body content of the primitive cobblestone area forming cells
(CAFC)-day 28 was increased to 140%, whereas the more committed cells
(CAFC-day 7, erythroid and granuloid progenitors) were increased to 500%.
This in vivo expansion resulted in a decreased 5-FU sensitivity of the
hematopoietic system. In particular, mice that had received 5-FU 24 hours
after discontinuation of growth factor pretreatment showed significantly
less toxicity of committed cell stages. Compared with mice not pretreated,
it appeared that in pretreated mice, 24 hours after 5-FU administration,
the absolute number, but also the fraction of surviving CAFC, was much
higher in both marrow and spleen. This was caused by a decrease in the
cycling activity of all primitive cell subsets. To explore the possible use
of this finding in a chemotherapeutic setting, we determined the interval
between two subsequent doses of 5-FU (160 mg/kg) that was required to
prevent drug- induced mortality. When control mice received a second dose
of 5-FU 7, 10, or 14 days after the first, respectively 0%, 20%, and 80%
survived. In contrast, 40% and 100% of mice that received SCF + IL-11
before the first dose of 5-FU, survived a second dose of 5-FU given
respectively after 7 or 10 days. To assess whether chemoprotection in this
setting could be ascribed to protection of the hematopoietic system, we
transplanted a high number of normal bone marrow cells (sufficient to
compensate for any hematopoietic deficiency) to normal and pretreated mice
after they had been administered 2 doses of 5-FU, given 7 days apart. Bone
marrow transplantation (BMT) could only rescue 50% of mice not pretreated,
showing that a significant part of the mortality was because of
nonhematologic toxicity. However, a BMT given to growth factor pretreated
mice saved all mice, indicating that in this setting SCF + IL-11 had
additional protective effects on cell systems other than hematopoiesis. In
conclusion, our study showed fundamental knowledge about the behavior of
primitive cells in vivo and has shown that manipulation of these and other
cell compartments with appropriate growth factors may confer resistance
against cytotoxic drugs.
Volume 87,
Issue 11,
pp. 4581-4588,
06/01/1996
Copyright © 1996 by The American Society of Hematology
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