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Total marrow failure induced by pegylated stem-cell factor administered
before 5-fluorouracil
G Molineux, A Migdalska, J Haley, GS Evans and TM Dexter
Department of Experimental Haematology, Paterson Institute for Cancer
Research, Christie Hospital, Withington, UK.
To examine the potential role of stem-cell factor (SCF) in cancer
chemotherapy, we have administered it to mice either before or after 5-
fluorouracil (5-FU). When polyethylene glycolated (PEG-ylated) SCF was
administered to mice before 5-FU, it had a significant sensitizing effect
on primitive bone marrow cells. Examination of the hematopoietic status of
these mice showed that the damage caused by 5-FU to both bone marrow and
spleen hematopoiesis was exaggerated when it was preceded by SCF. SCF given
before each of two 5-FU treatments at 7-day intervals resulted in the death
of all treated mice. The time of death and hematopoietic status of these
animals are compatible with the onset of hypoplastic marrow failure leading
to pancytopenia and death. SCF given after 5-FU had little impact either on
the initial degree of hematopoietic damage or subsequent recovery. Gut
populations were similarly sensitized to 5-FU by prior treatment with SCF,
and the damage caused to intestinal populations was greater than that
resulting from 5-FU alone. This indicates that the different tissues may be
similarly sensitized by SCF. The sensitizing effect of SCF was reversed by
concurrent administration of transforming growth factor (TGF)-beta 3, and
survival of the majority of the mice was ensured. Examination of
hematopoiesis in mice treated concurrently with SCF and TGF-beta 3 showed
that the degree of marrow and spleen damage had reverted to that caused by
5-FU alone. In further experiments, 100% survival and normal hematopoiesis
could be attained by transplantation of 1 million syngeneic bone marrow
cells 24 hours after 5-FU treatment following SCF sensitization. These data
indicate that PEG-ylated SCF can sensitize normally resistant hematopoietic
and gut stem cells to the effects of 5- FU. This sensitization resulted in
effective eradication of hematopoiesis in SCF-pretreated/5-FU-treated
animals and their subsequent death from marrow failure. These findings
imply that SCF pretreatment may represent a novel method of increasing the
effectiveness of conventional chemotherapy, making marrow ablation more
effective without drug dose escalation and perhaps sensitizing some tumor
cells to the effects of therapy.
Volume 83,
Issue 12,
pp. 3491-3499,
06/15/1994
Copyright © 1994 by The American Society of Hematology
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