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, Hiroshi Miyazaki

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)37-45
Number of pages9
JournalBlood
Volume91
Issue number1
Publication statusPublished - 1998 Jan 1
Externally publishedYes

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Recovery
Injections
Irradiation
Granulocyte Colony-Stimulating Factor
Blood
Cells
Megakaryocytes
Thrombocytopenia
Anemia
Blood Cells
Bone
Leukocytes
polyethylene glycol-recombinant human megakaryocyte growth and development factor
Thrombopoiesis
Macrophage Colony-Stimulating Factor
Pharmacokinetics
Whole-Body Irradiation
Hematopoiesis
Leukopenia
Platelets

ASJC Scopus subject areas

  • Hematology

Cite this

Multilineage hematopoietic recovery by a single injection of pegylated recombinant human megakaryocyte growth and development factor in myelosuppressed mice. / Shibuya, Kazunori; Akahori, Hiromichi; Takahashi, Kazumi; Tahara, Emiko; Kato, Takashi; Miyazaki, Hiroshi.

In: Blood, Vol. 91, No. 1, 01.01.1998, p. 37-45.

Research output: Contribution to journalArticle

Shibuya, Kazunori ; Akahori, Hiromichi ; Takahashi, Kazumi ; Tahara, Emiko ; Kato, Takashi ; Miyazaki, Hiroshi. / Multilineage hematopoietic recovery by a single injection of pegylated recombinant human megakaryocyte growth and development factor in myelosuppressed mice. In: Blood. 1998 ; Vol. 91, No. 1. pp. 37-45.
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