Systemic effects of pegylated recombinant human megakaryocyte growth and development factor in combination with recombinant murine granulocyte colony-stimulating factor in a murine model of myelosuppression.

摘要

Megakaryocyte growth and development factor (MGDF) stimulates megakaryopoiesis and thrombopoiesis in vivo. Previous studies indicate that administration of pegylated recombinant human (PEG-rHu) MGDF in combination with recombinant murine granulocyte colony-stimulating factor (rMuG-CSF) prevented lethality and reduced hematotoxicity in carboplatin-treated/irradiated mice, a disease-state animal model of radio-chemotherapy. In the current study we have further characterized the effects of PEG-rHuMGDF in combination with rMuG-CSF with respect to clinical chemistry, hematology variables, and histologic evaluations to determine whether any potential toxicological interaction exists both in normal and myelosuppressed mice. Myelosuppression and subsequent thrombocytopenia in mice was induced with a combination of a single intraperitoneal injection of 1.25 mg carboplatin followed 4 h later with sublethal gamma irradiation exposure of 500 rad. Both normal and carboplatin-treated/irradiated mice were administered daily subcutaneous injections of 50 micrograms/kg PEG-rHuMGDF alone and in combination with 10 micrograms/kg rMuG-CSF for 21 consecutive days. Administration of PEG-rHuMGDF alone or in combination with rMuG-CSF to carboplatin-treated/irradiated mice increased survival 70 and 100%, respectively, and accelerated platelet recovery. Microscopic examination of nonhematopoietic organs showed no evidence of any morphological changes in normal and carboplatin-treated/irradiated animals. In hematopoietic organs clinically significantly increased granulopoiesis and megakaryopoiesis, as well as extramedullary granulopoiesis within the mandibular and mesenteric lymph nodes, were present. The erythroid line was unaffected by cytokine treatment. In normal, non-carboplatin-treated/irradiated mice, platelet counts increased 6 and 12-fold above baseline in the groups administered PEG-rHuMGDF alone or in combination with rMuG-CSF, respectively. The results of this study provide a basis for coadministration of PEG-rHuMGDF with Filgrastim (rHuG-CSF) in the clinical treatment of myelosuppression induced by radiation and chemotherapy.