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Multilineage Hematopoietic Recovery by a Single Injection of
Pegylated Recombinant Human Megakaryocyte Growth and Development
Factor in Myelosuppressed Mice
Kazunori Shibuya,
Hiromichi Akahori,
Kazumi Takahashi,
Emiko Tahara,
Takashi Kato, and
Hiroshi Miyazaki
From the Pharmaceutical Research Laboratory, Kirin Brewery Co,
Takasaki, Japan.
Previous studies have shown that daily multiple administration of
pegylated recombinant human megakaryocyte growth and development factor
(PEG-rHuMGDF) markedly stimulates thrombopoiesis and effectively ameliorates thrombocytopenia, and in most cases anemia and neutropenia, in myelosuppressed animals. In this study, we evaluated the effects of
a single intravenous injection of PEG-rHuMGDF on hematopoietic recovery
after sublethal total-body irradiation in mice. A single injection of
PEG-rHuMGDF (1 to 640 µg/kg) 1 hour after irradiation accelerated
platelet, red blood cell (RBC), and white blood cell (WBC) recovery in
a dose-dependent fashion. In the bone marrow of vehicle-treated mice,
megakaryocytic, erythroid, and myeloid progenitors, as well as day 12 colony-forming unit-spleen (CFU-S), were dramatically decreased much
earlier than the nadirs of peripheral blood cells, whereas
megakaryocytes were modestly decreased. Treatment with PEG-rHuMGDF (80 µg/kg, an optimal dose) 1 hour after irradiation resulted in more
rapid recovery of these four hematopoietic progenitors and also
significantly facilitated megakaryocyte recovery. In addition, the same
PEG-rHuMGDF administration schedule expanded bone marrow cells capable
of rescuing lethally irradiated recipient mice. As the interval between
irradiation and PEG-rHuMGDF treatment was longer, its effects on
hematopoietic recovery were attenuated. In contrast to the effects of
PEG-rHuMGDF, a single injection of recombinant human granulocyte
colony-stimulating factor (rhG-CSF) 1 hour after irradiation
exclusively accelerated WBC recovery, but only to a similar extent as
PEG-rHuMGDF (80 µg/kg) treatment even when rhG-CSF doses were
escalated to 1,000 µg/kg. This appeared related to different
pharmacokinetics of these two factors after a single injection in
irradiated mice. The concentrations of PEG-rHuMGDF after injection
persisted in the plasma for a longer time compared with rhG-CSF. These
results indicate that a single injection of PEG-rHuMGDF at an early
time after irradiation is able to effectively improve thrombocytopenia,
anemia, and leukopenia with concomitant accelerated recovery of both
primitive and committed hematopoietic progenitors in irradiated mice.
Our data also show that compared with the rhG-CSF shown to exert
multilineage effects on hematopoiesis, PEG-rHuMGDF has more
wide-ranging effects on peripheral blood cell recovery.
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 37-45
© 1998 by The American Society of Hematology.
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