The prolonged hematologic effects of a single injection of PEG-rHuMGDF in normal and thrombocytopenic mice

A single injection of greater than or equal to 10 mu g/kg PEG-rHuMGDF in mi ce causes a dose-dependent increase in circulating platelets beginning on d ay 3 and peaking on days 5-6, The mean platelet volume and platelet distrib ution width at doses greater than or equal to 100 mu g/kg initially increas e in a dose-dependent fashion and later decrease, However, the mean platele t volume does not change when platelets are incubated with PEG-rHuMGDF in v itro, The number of marrow megakaryocytes increases in a dose-dependent fas hion as early as day 1 and peaks on day 3, Marrow megakaryocyte colony-form ing units (CFU-Meg) do not increase on days 1-3 at a dose of 100 mu g/kg (a dose that increases platelet numbers two- to threefold and may be clinical ly relevant), but the relative frequency of high ploidy megakaryocytes and the proportion of large marrow megakaryocytes (29-50 mu m in diameter) incr eases. After a dose of 1,000 mu g/kg the percentage of megakaryocytes in mi tosis peaks at 24-48 hours and the percentage of megakaryocytes incorporati ng BrdU is maximal at 48 hours, the relatively delayed peak of BrdU incorpo ration most likely representing endomitosis, The relative frequency of type II and III megakaryocytes peaks on days 3 and 4, respectively. Pharmacokin etic analysis of PEG-rHuMGDF shows peak serum concentrations at 2-4 hours a nd a terminal half-life of 11.4 +/- 2.5 hours, A single injection of PEG-rH uMGDF ameliorates carboplatin-induced megakaryocytopenia and thrombocytopen ia in a dose-response dependent fashion, In conclusion, a single injection of PEG-rHuMGDF increases megakaryocyte and platelet production in normal an d myelosuppressed mice, (C) 1999 International Society for Experimental Hem atology, Published by Elsevier Science Inc.