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PEG-rHuMGDF promotes multilineage hematopoietic recovery in myelosuppressed mice
T R Ulich1, J del Castillo, G Senaldi
1Amgen, Thousand Oaks, CA 91320, USA. tulich@amgen.com
Abstract:
PEG-rHuMGDF administered to normal mice is a lineage-specific growth factor for megakaryocytes and platelets as judged by morphologic examination of hematologic cells in marrow and peripheral blood smears. The purpose of this study was to document that PEG-rHuMGDF in myelosuppressed mice promotes multilineage hematopoietic recovery. High-dose 5-fluorouracil (5-FU) in mice results in profound myelosuppression and 0-30% survival. Mice receiving a single dose of PEG-rHuMGDF (1000 microg/kg) 1 day after 5-FU (225 mg/kg) demonstrate an increased survival (76% vs 27% in control mice at 14 days). Compared to surviving controls, PEG-rHuMGDF-treated mice not only show the expected higher platelet counts, but also increased marrow colony-forming unit granulocyte-macrophage, increased multilineage marrow cellularity, and increased neutrophil, monocyte, and lymphocyte counts in peripheral blood. PEG-rHuMGDF- and vehicle-treated mice both develop hepatic abscesses after 5-FU treatment, but the abscesses in the PEG-rHuMGDF-treated mice contain more neutrophils, suggesting that myeloid reconstitution contributes to their survival. Furthermore, survival in 5-FU-treated mice is significantly improved by granulocyte colony-stimulating factor and antibiotics, suggesting that infection rather than thrombocytopenia is the predominant cause of death. PEG-rHuMGDF after 5-FU promotes survival accompanied by accelerated lymphohematopoietic repopulation, suggesting that PEG-rHuMGDF, a lineage-specific thrombopoietic factor in normal mice, promotes multilineage hematopoietic recovery in myelosuppressed mice.
Insights
PEG-ylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) significantly improves survival in mice after chemotherapy. This thrombopoietic factor promotes multilineage hematopoietic recovery, enhancing immune cell counts and overall survival.
Area of Science:
- Hematology
- Immunology
- Pharmacology
Background:
- PEG-rHuMGDF is a lineage-specific growth factor for megakaryocytes and platelets in normal mice.
- High-dose 5-fluorouracil (5-FU) causes profound myelosuppression and high mortality in mice.
- Infection, rather than thrombocytopenia, is the primary cause of death in 5-FU-treated mice.
Purpose of the Study:
- To investigate the efficacy of PEG-rHuMGDF in promoting multilineage hematopoietic recovery in myelosuppressed mice.
- To evaluate the impact of PEG-rHuMGDF on survival rates following 5-FU-induced myelosuppression.
Main Methods:
- Mice were treated with high-dose 5-FU followed by a single dose of PEG-rHuMGDF or vehicle.
- Hematologic cell morphology, peripheral blood counts, and marrow cellularity were analyzed.
- Survival rates and the presence of hepatic abscesses were monitored.
Main Results:
- PEG-rHuMGDF administration increased survival from 27% to 76% in 5-FU-treated mice.
- Treated mice showed higher platelet counts, increased marrow colony-forming unit granulocyte-macrophage, and enhanced multilineage marrow cellularity.
- Peripheral blood showed increased neutrophil, monocyte, and lymphocyte counts, with more neutrophils in hepatic abscesses.
Conclusions:
- PEG-rHuMGDF promotes survival in myelosuppressed mice by accelerating lymphohematopoietic repopulation.
- This thrombopoietic factor demonstrates efficacy in promoting multilineage hematopoietic recovery beyond its lineage-specific effects.
- Myeloid reconstitution, supported by PEG-rHuMGDF, contributes to improved survival in 5-FU-treated mice.