In vivo effects of pegylated recombinant human megakaryocyte growth and development factor on hematopoiesis in normal mice.
The in vivo effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated molecule of recombinant human thrombopoietin modified with polyethylene glycol, were investigated in normal Balb/c mice. PEG-rHuMGDF was more potent in producing platelets and the dose-response curve was steeper compared with the case of the nonpegylated form of this molecule. Five consecutive injections with PEG-rHuMGDF caused a dose-dependent increase in peripheral platelet counts with a peak on day 8. There was a dose-dependent rise in platelet counts on day 8 at daily doses from 0.333 to 30 micrograms/kg. Intermediate doses of PEG-rHuMGDF (1.111 to 10 micrograms/kg/day) caused a significant decrease in mean platelet volume, and conversely, higher doses of PEG-rHuMGDF (30 to 270 micrograms/kg/day) induced a dose-dependent increase in mean platelet volume. There was a dose-dependent decrease in hemoglobin concentration with a minimum on day 8 but no significant reduction in reticulocyte counts following PEG-rHuMGDF administration. White blood cell counts were unchanged by PEG-rHuMGDF treatment. Marrow megakaryocyte size enlarged to 1.5-fold and the number of marrow megakaryocytes increased to sixfold by consecutive administration of PEG-rHuMGDF at 30 micrograms/kg/day. A twofold increase in the number of marrow megakaryocytic progenitor cells (colony-forming units-megakaryocyte) was also observed. Marrow erythroid progenitor (colony-forming units-erythroid) counts decreased but splenic colony-forming units-erythroid, marrow and splenic erythro/myeloid progenitor cell counts, and splenic granulocyte/macrophage progenitor cell counts increased with PEG-rHuMGDF treatment. Marrow and splenic erythroid burst-forming cells were unchanged. These results indicate that PEG-rHuMGDF, a truncated molecule of thrombopoietin, is a potent stimulator for megakaryopoiesis and thrombopoiesis, and also affects the development of other hematopoietic cells in normal mice.
Kabaya
K
K
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Akahori
H
H
Shibuya
K
K
Nitta
Y
Y
Ida
M
M
Kusaka
M
M
Kato
T
T
Miyazaki
H
H
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006410:Hematopoiesis / Q000187:drug effects*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010976:Platelet Count / Q000187:drug effects; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000494:pharmacology; D017701:Reticulocyte Count / Q000187:drug effects; D013926:Thrombopoietin / Q000008:administration & dosage / Q000494:pharmacology*
D006454:Hemoglobins; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D013926:Thrombopoietin