Effects of Pegylated Recombinant Human Megakaryocyte Growth and Development Factor on Thrombocytopenia Induced by a New Myelosuppressive Chemotherapy Regimen in Mice

Abstract

Abstract. 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 PEGrHuMGDF on alternate days or once a week after chemotherapy was almost as effective as consecutive administration in improving thrombocytopenia. Combined administration of PEGrHuMGDF and rHuG-CSF had an addictive effect on improvement of thrombocytopenia and neutropenia. These results suggest that PEGrHuMGDF is a therapeutically effective agent in the treatment of thrombocytopenia associated with chemotherapy.

Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug

“…5 Thrombopoietin (TPO) is known to be a critical regulator of hematopoiesis. [8][9][10] The TPO receptor c-mpl is expressed on HSCs, 11 and knockout mice that lack c-mpl are deficient in HSCs. 12,13 Eltrombopag is an oral TPO receptor agonist and was originally developed to stimulate thrombopoiesis in patients with immune thrombocytopenias.…”

Pharmacokinetics and Hematological Effects of the PEGylated Thrombopoietin Peptide Mimetic GW395058 in Rats and Monkeys After Intravenous or Subcutaneous Administration

“…Two forms of the recombinant human protein have been investigated: full-length glycosylated recombinant human protein (rHuTPO) [5] and PEGylated megakaryocyte growth and development factor (PEG-rHuMGDF) [6]. In mice, dogs, and primates [7][8][9][10][11][12][13][14], rHuTPO and PEG-rHuMGDF promote platelet production and reduce chemotherapy-induced thrombocytopienia. Unfortunately, evidence of TPO-neutralizing antibodies in patients participating in cancer and platelet donor clinical trials forced the discontinuation of PEG-rHuMGDF development [15].…”

Involvement of the TGF-.BETA.1 Derived from Megakaryocyte in the PEG-rHuMGDF-Induced Myelofibrosis and Bone Formation.

“…PEG-rHuMGDF has been reported to cause an increase of the circulating platelet counts in normal mice, normal rats, and normal rhesus monkey 1,[5][6][7] . PEG-rHuMGDF prevented thrombocytopenia in many animal models [8][9][10][11][12][13] . Therefore, PEG-rHuMGDF is expected to be effective in stimulating thrombopoiesis in clinical setting after myelosuppression.…”