Thrombopoietin, the endogenous
c-Mpl ligand, is a novel lineage-specific hematopoietic factor that plays a pivotal role in the regulation of megakaryocytopoiesis and thrombopoiesis. In this study, we examined the effects of
pegylated recombinant human megakaryocyte growth and development factor (
PEG-rHuMGDF), a truncated molecule of recombinant human
c-Mpl ligand derivatized with
polyethylene glycol, on myelosuppressive
chemotherapy-induced
thrombocytopenia in mice. We developed a new murine model of
thrombocytopenia induced by i.v.
injections of
mitomycin C (MMC) for two consecutive days. In control mice, platelet counts began to decrease on day 6, reached a nadir of less than 5% of basal level on day 14, and could not recover to basal level by day 26. Administration of
PEG-rHuMGDF greatly enhanced recovery of the number of megakaryocyte progenitor cells and the megakaryocytes in bone marrow, and markedly reduced the severity of
thrombocytopenia; it also accelerated platelet recovery in a dose-dependent manner in myelosuppressed mice. Mice receiving consecutive administration of higher doses of
PEG-rHuMGDF showed no
thrombocytopenia but rather had platelet counts being increased over basal level. Although absolute neutrophil counts and red cell counts also were decreased following MMC treatment, administration of
PEG-rHuMGDF also improved
neutropenia and
anemia. Administration of
PEG-rHuMGDF on alternate days or once a week after
chemotherapy was almost as effective as consecutive administration in improving
thrombocytopenia. Combined administration of
PEG-rHuMGDF and rHuG-CSF had an additive effect on improvement of
thrombocytopenia and
neutropenia. These results suggest that
PEG-rHuMGDF is a therapeutically effective agent in the treatment of
thrombocytopenia associated with
chemotherapy.