INFLUENCE OF RHG-CSF SCHEDULING ON MEGAKARYOCYTOPOIETIC RECOVERY FOLLOWING 5-FLUOROURACIL-INDUCED HEMATOTOXICITY IN SPLENECTOMIZED B6D2F1 MICE

Recombinant human granulocyte colony-stimulating factor, rhG-CSF, is w idely applied to ameliorate neutropenia following chemotherapy. Howeve r, rhG-CSF can exert negative effects on megakaryocytopoiesis that mig ht cause a delay of megakaryocyte recovery. Therefore, the present stu dy was designed to test different rhG-CSF administration protocols wit h regard to their megakaryocytic inhibitory potential in a 5-fluoroura cil (5-FU)-induced experimental model system. Splenectomized B6D2F1 mi ce received a single injection of 5-FU (150 mg/kg) on day 0 followed b y 50 mu g/kg/day rhG-CSF given daily for either zero, four, or eight d ays. Five days after 5-FU, bone marrow and blood hematopoiesis were re duced significantly when compared with controls, independent of whethe r or not animals received rhG-CSF. However, nine days after 5-FU, gran ulopoietic recovery from 5-FU-induced toxicity was faster for rhG-CSF- treated versus untreated mice as demonstrated by higher values for col ony forming unit-granulocyte macrophage (CFU-GM) and granulocytes (CFU -GM:7.2 +/- 0.4 versus 5 +/- 0.6 x 10(4)/femur, granulocytes: 4.3 +/- 2 versus 1.4 +/- 0.4 x 10(5)/ml, respectively). Furthermore, significa nt mobilization of CFU-megakaryocyte (CFU-Meg) and CFU-GM into the per ipheral blood was induced by the eight-day administration of rhG-CSF f ollowing 5-FU (day 9: 911 +/- 102 CFU-Meg/ml, 2330 +/- 152 CFU-GM/ml). However, megakaryocytic cells in these same mice were considerably lo wer when compared viith those of animals receiving no rhG-CSF (CFU-Meg : 2.7 +/- 0.2 x 10(3) versus 4.2 +/- 0.2 x 10(3)/femur; small acetylch olinesterase positive (SAChE(+)) cells: 4.9 +/- 0.3 x 10(3) versus 7.3 +/- 0.9 x 10(3)/femur; megakaryocytes: 2.5 +/- 0.2 x 10(3) versus 4.1 +/- 0.7 x 10(3)/femur; platelets: 2.67 +/- 0.5 x 10(9) versus 3.1 +/- 0.5 x 10(9)/ml, respectively). On the other hand, the shortening of t he rhG-CSF treatment from eight to four days caused a rapid granulopoi etic recovery comparable to animals receiving eight days of G-CSF with no significant delay in megakaryocytic recovery when compared with mi ce treated with 5-FU alone; however, with four days of rhG-CSF, the mo bilization of CFU into the peripheral blood was significantly less eff ective, Taken together, the results showed that a shortening of rhG-CS F treatment after chemotherapy is capable of ameliorating neutropenia without negatively affecting megakaryocytopoietic recovery. If, howeve r, maximum recruitment of CFU into the peripheral blood circulation by rhG-CSF far subsequent harvest and transplantation is needed, any sho rtening of rhG-CSF administration is not advisable.