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Influence of rhG-CSF Scheduling on Megakaryocytopoietic Recovery following 5-Fluorouracil-Induced Hematotoxicity in Splenectomized B₆D₂F₁ Mice

Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA;

Key Words. Megakaryocytopoiesis • rhG-CSF • Mice • 5-Fluorouracil

Dr. Alexander Nakeff, Division of Hematology and Oncology, Wayne State University, School of Medicine, 550 East Canfield Avenue, Lande MRB 15, Detroit, MI 48201, USA.

Recombinant human granulocyte colony-stimulating factor, rhG-CSF, is widely applied to ameliorate neutropenia following chemotherapy. However, rhG-CSF can exert negative effects on megakaryocytopoiesis that might cause a delay of megakaryocyte recovery. Therefore, the present study was designed to test different rhG-CSF administration protocols with regard to their megakaryocytic inhibitory potential in a 5-fluorouracil (5-FU)-induced experimental model system. Splenectomized B₆D₂F₁ mice received a single injection of 5-FU (150 mg/kg) on day 0 followed by 50 µg/kg/day rhG-CSF given daily for either zero, four, or eight days. Five days after 5-FU, bone marrow and blood hematopoiesis were reduced significantly when compared with controls, independent of whether or not animals received rhG-CSF. However, nine days after 5-FU, granulopoietic recovery from 5-FU-induced toxicity was faster for rhG-CSF-treated versus untreated mice as demonstrated by higher values for colony forming unit-granulocyte macrophage (CFU-GM) and granulocytes (CFU-GM: 7.2 ± 0.4 versus 5 ± 0.6 x 10⁴/femur, granulocytes: 4.3 ± 2 versus 1.4 ± 0.4 x 10⁵/ml, respectively). Furthermore, significant mobilization of CFU-megakaryocyte (CFU-Meg) and CFU-GM into the peripheral blood was induced by the eight-day administration of rhG-CSF following 5-FU (day 9: 911 ± 102 CFU-Meg/ml, 2330 ± 152 CFU-GM/ml). However, megakaryocytic cells in these same mice were considerably lower when compared with those of animals receiving no rhG-CSF (CFU-Meg: 2.7 ± 0.2 x 10³ versus 4.2 ± 0.2 x 10³/femur; small acetylcholinesterase positive (SAChE⁺) cells: 4.9 ± 0.3 x 10³ versus 7.3 ± 0.9 x 10³/femur; megakaryocytes: 2.5 ± 0.2 x 10³ versus 4.1 ± 0.7 x 10³/femur; platelets: 2.67 ± 0.5 x 10⁹ versus 3.1 ± 0.5 x 10⁹/ml, respectively). On the other hand, the shortening of the rhG-CSF treatment from eight to four days caused a rapid granulopoietic recovery comparable to animals receiving eight days of G-CSF with no significant delay in megakaryocytic recovery when compared with mice treated with 5-FU alone; however, with four days of rhG-CSF, the mobilization of CFU into the peripheral blood was significantly less effective. Taken together, the results showed that a shortening of rhG-CSF treatment after chemotherapy is capable of ameliorating neutropenia without negatively affecting megakaryocytopoietic recovery. If, however, maximum recruitment of CFU into the peripheral blood circulation by rhG-CSF for subsequent harvest and transplantation is needed, any shortening of rhG-CSF administration is not advisable.

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