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Host conditioning with 5-fluorouracil and kit-ligand to provide for
long-term bone marrow engraftment
R van Os, D Dawes, JM Mislow, A Witsell and PM Mauch
Department of Radiation Oncology, Harvard Medical School, Boston, MA 02215,
USA.
Administration of kit-ligand (KL) before and after doses of 5- fluorouracil
(5-FU) results in marrow failure in mice, presumably because of enhanced
KL-induced cycling of stem cells, which makes them more susceptible to the
effects of 5-FU. In attempt to capitalize on this effect on stem cells, we
studied the ability of KL and 5-FU to allow stable donor engraftment of
congenically marked marrow in a C57BL/6 (B6) mouse model. KL was
administered subcutaneously at 50 microg/kg, 21 hours and 9 hours before
and 3 hours after each of two doses of 5-FU (125 mg/kg) given 7 days apart
to B6-recipients. Animals then received three injections of 10(7) congenic
B6-Gpi-1a-donor bone marrow cells at 24, 48, and 72 hours after the second
5-FU dose. A separate group of animals received a single dose of either 1 x
10(7) or 3 x 10(7) donor marrow cells 24 hours after the last 5-FU dose.
The level of engraftment was measured from Gpi-phenotyping at 1, 3, 6, and
8 months in red blood cells (RBCs) and at 8 months by phenotyping cells
from the thymus, spleen, and marrow. Percent donor engraftment in RBCs
appeared stable after 6 months. The percent donor engraftment in RBCs at 8
months was significantly higher in KL + 5-FU prepared recipients (33.0 +/-
2.7), compared with 5-FU alone (18.5 +/- 2.6, P < .0005), or saline
controls (17.8 +/- 1.7, P < .0001). In an additional experiment,
granulocyte colony-stimulating factor (100 microg/dose) was added to a
reduced dose of KL (12.5 microg/dose); engraftment was similar to KL alone.
At 8 months after transplantation the levels of engraftment in other
tissues such as bone marrow, spleen, and thymus correlated well with
erythroid engraftment to suggest that multipotent long-term repopulating
stem cells had engrafted in these animals. There are concerns for the
toxicity of total body irradiation (TBI)- or busulfan- based regimens in
young recipients of syngeneic or transduced autologous marrow who are
transplanted for correction of genetic disease. In these recipients
complete donor engraftment may not be needed. The results with KL and 5-FU
are encouraging for the further refinement of non-TBI, nonbusulfan
techniques to achieve stable mixed chimerism.
Volume 89,
Issue 7,
pp. 2376-2383,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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