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

Megakaryocyte growth and development factor (MGDF) stimulates megakary opoiesis and thrombopoiesis in vivo. Previous studies indicate that ad ministration of pegylated recombinant human (PEG-rHu) MGDF in combinat ion with recombinant murine granulocyte colony-stimulating factor (rMu G-CSF) prevented lethality and reduced hematotoxicity in carboplatin-t reated/irradiated mice, a disease-state animal model of radio-chemothe rapy, In the current study we have further characterized the effects o f PEG-rHuMGDF in combination with rMuG-CSF with respect to clinical ch emistry, hematology variables, and histologic evaluations to determine whether any potential toxicological interaction exists both in normal and myelosuppressed mice. Myelosuppression and subsequent thrombocyto penia in mice was induced with a combination of a single intraperitone al injection of 1.25 mg carboplatin followed 4 h later with sublethal gamma irradiation exposure of 500 rad, Both normal and carboplatin-tre ated/irradiated mice were administered daily subcutaneous injections o f 50 mu g/kg PEG-rHuMGDF alone and in combination with 10 mu g/kg rMuG -CSF for 21 consecutive days. Administration of PEG-rHuMGDF alone or i n combination with rMuG-CSF to carboplatin-treated/irradiated mice inc reased survival 70 and 100%, respectively, and accelerated platelet re covery, Microscopic examination of nonhematopoietic organs showed no e vidence of any morphological changes in normal and carboplatin-treated / irradiated animals. In hematopoietic organs clinically significantly increased granulopoiesis and megakaryopoiesis, as well as extramedull ary granulopoiesis within the mandibular and mesenteric lymph nodes, w ere present. The erythroid line was unaffected by cytokine treatment. In normal, non-carboplatin-treated/irradiated mice, platelet counts in creased 6 and 12-fold above baseline in the groups administered PEG-rH uMGDF alone or in combination with rMuG-CSF, respectively, The results of this study provide a basis for coadministration of PEG-rHuMGDF wit h Filgrastim (rHuG-CSF) in the clinical treatment of myelosuppression induced by radiation and chemotherapy. (C) 1998 Society of Toxicology.