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ORIGINAL PAPER |
a Division of Clinical Research, Fred Hutchinson Cancer Research Center and
b Department of Pediatrics. University of Washington School of Medicine. Seattle, Washington, USA;
c Developmental Hematology Department, Amgen, Thousand Oaks, California, USA; and
d University of Washington Regional Primate Research Center, Seattle, Washington, USA
Key Words. Thrombopoietin • Hematopoiesis • Chemotherapy • Bone Marrow • Platelets • Colony-forming cells • Baboons (papio species)
Dr. Robert G. Andrews, Pediatric Oncology Program, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, USA.
Megakaryocyte growth and development factor (MGDF) is a ligand for c-mpl and a member of the hematopoietic growth factor superfamily. Recombinant murine MGDF specifically stimulates thrombopoiesis in mice. Recombinant human (rHu) MGDF stimulates megakaryocytic differentiation of baboon CD 34+ marrow cells in vitro. Therefore, we determined the in vivo biological effects of rHuMGDF administered to normal baboons in the absence and presence of myelosuppression with 5-fluorouracil (5-FU). rHuMGDF was administered to normal baboons as single s.c. injection at doses of 1, 10, 25 and 50 µg/kg/day for 10 days and, as a control, heat-inactivated MGDF was administered at a dose of 10 µg/kg/day. Platelet counts were markedly increased in all animals administered native rHuMGDF but not in animals given heat-inactivated rHuMGDF. Platelet counts began to increase between three and six days after starting rHuMGDF administration and the maximum average increases were 1.7-, 3.4-, 5.1- and 4.0-fold above baseline in animals administered 1, 10, 25 and 50 µg/kg/day, respectively. Maximum platelet counts were reached between 7 and 10 days after starting rHuMGDF and maintained for four days after the last dose. Thereafter, platelet counts decreased, reaching stable pretreatment values between 11 and 14 days after the last dose of rHuMGDF. No changes in red cell mass, peripheral blood white blood cell counts or differentials were observed during rHuMGDF treatment. For animals administered 10, 25 and 50 µg/kg/day of rHuMGDF, megakaryocytes increased more than threefold in marrow, were markedly enlarged, and had increased numbers of lobes. Overall marrow cellularity remained unchanged, as did red cell and white cell morphology. No marrow fibrosis was detected. Progenitor cells were not increased in marrow but did increase modestly in the peripheral blood, associated with increased numbers of CD34+ cells in circulation.
Following a single dose of 5-FU (120 mg/kg) animals were given either saline or pegylated (PEG) rHuMGDF (25 µg/kg/day) for 14 days. Platelet counts recovered to baseline by 13.8 ± 1.8 days for PEG-rHuMGDF-treated baboons compared with 16.8 ± 0.6 days for saline treated controls. Marrow biopsies revealed more rapid recovery of overall marrow cellularity and megakaryocytes in PEG-rHuMGDF-treated animals compared with controls. Thus, rHuMGDF specifically stimulates thrombopoiesis in normal and myelosuppressed baboons. rHuMGDF may be useful for stimulating thrombopoiesis in humans in clinical settings after myelosuppression.
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