EFFECTS OF PEGYLATED RECOMBINANT HUMAN MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR ON THROMBOCYTOPENIA INDUCED BY A NEW MYELOSUPPRESSIVE CHEMOTHERAPY REGIMEN IN MICE

Thrombopoietin, the endogenous c-Mpl ligand, is a novel lineage-specif ic hematopoietic factor that plays a pivotal role in the regulation of megakaryocytopoiesis and thrombopoiesis. In this study, we examined t he effects of pegylated recombinant human megakaryocyte growth and dev elopment factor (PEG-rHuMGDF), a truncated molecule of recombinant hum an c-Mpl ligand derivatized with polyethylene glycol, on myelosuppress ive chemotherapy-induced thrombocytopenia in mice. We developed a new murine model of thrombocytopenia induced by i.v. injections of mitomyc in 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 l evel on day 14, and could not recover to basal level by day 26. Admini stration of PEG-rHuMGDF greatly enhanced recovery of the number of meg akaryocyte progenitor cells and the megakaryocytes in bone marrow, and markedly reduced the severity of thrombocytopenia; it also accelerate d platelet recovery in a dose-dependent manner in myelosuppressed mice . Mice receiving consecutive administration of higher doses of PEG-rHu MGDF showed no thrombocytopenia but rather had platelet counts being i ncreased over basal level. Although absolute neutrophil counts and red cell counts also were decreased following MMC treatment, administrati on of PEG-rHuMGDF also improved neutropenia and anemia. Administration of PEG-rHuMGDF on alternate days or once a week after chemotherapy wa s almost as effective as consecutive administration in improving throm bocytopenia. Combined administration of PEG-rHuMGDF and rHuG-CSF had a n 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 chemotherap y.