PROPHYLACTIC PRETREATMENT OF MICE WITH HEMATOPOIETIC GROWTH-FACTORS INDUCES EXPANSION OF PRIMITIVE CELL COMPARTMENTS AND RESULTS IN PROTECTION AGAINST 5-FLUOROURACIL-INDUCED TOXICITY
G. Dehaan et al., PROPHYLACTIC PRETREATMENT OF MICE WITH HEMATOPOIETIC GROWTH-FACTORS INDUCES EXPANSION OF PRIMITIVE CELL COMPARTMENTS AND RESULTS IN PROTECTION AGAINST 5-FLUOROURACIL-INDUCED TOXICITY, Blood, 87(11), 1996, pp. 4581-4588
The aim of this study was to expand the primitive and committed hemato
poietic 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 cel
ls, present before 5-FU administration. In addition, we hypothesized t
hat an enhanced number of primitive and progenitor cells would result
in a reduced cycling activity, ie, 5-FU sensitivity, of these same cel
ls, due to normal physiological feedback loops. Administration of stem
cell factor (SCF) plus interleukin-11 (IL-11) to mice was shown to re
sult in expansion of the various immature cell compartments in marrow
and, in particular, spleen. The total body content of the primitive co
bblestone area forming cells (CAFC)-day 28 was increased to 140%, wher
eas the more committed cells (CAFC-day 7, erythroid and granuloid prog
enitors) 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 ce
ll stages. Compared with mice not pretreated, it appeared that in pret
reated mice, 24 hours after 5-FU administration, the absolute number,
but also the fraction of surviving CAFC, was much higher in both marro
w and spleen. This was caused by a decrease in the cycling activity of
all primitive cell subsets. To explore the possible use of this findi
ng in a chemotherapeutic setting, we determined the interval between t
wo subsequent doses of 5-FU (160 mg/kg) that was required to prevent d
rug-induced mortality. When control mice received a second dose of 5-F
U 7, 10, or 14 days after the first, respectively 0%, 20%, and 80% sur
vived. In contrast, 40% and 100% of mice that received SCF + IL-11 bef
ore the first dose of 5-FU, survived a second dose of 5-FU given respe
ctively after 7 or 10 days. To assess whether chemoprotection in this
setting could be ascribed to protection of the hematopoietic system, w
e transplanted a high number of normal bone marrow cells (sufficient t
o compensate for any hematopoietic deficiency) to normal and pretreate
d 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 fac
tor pretreated mice saved all mice, indicating that in this setting SC
F + 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 manip
ulation of these and other cell compartments with appropriate growth f
actors may confer resistance against cytotoxic drugs. (C) 1996 by The
American Society of Hematology.