Kinetics of neutrophil production in normal and neutropenic animals duringthe response to filgrastim (r-metHu G-CSF) or filgrastim SD/01 (PEG-r-metHu G-CSF)

Filgrastim G-CSF has a short, biologically active half-life, and its effect ive use depends on repeated inoculations. A major aim, therefore, has been to develop a once-per-chemotherapy cycle formulation. To this end, a polyet hylene glycolylated form of Fligrastim, known as SD/01, has been developed. In this study, we compared the cellular kinetics of granulocyte production in mice stimulated with SD/01 and granulocyte colony-stimulating factor (G -CSF). Mice were injected with a single dose of SD/01 (1 mg/kg) or G-CSF (1 25 mug/kg) twice per day for 4 days, Mice rendered leukopenic with a single injection of cyclophosphamide (200 mg/kg) and temozolomide (90 mg/kg) were similarly treated at their 3-day neutrophil nadir. Tritiated thymidine was injected for autoradiographic labeling studies, Bone marrow labeling indic es and the release of labeled neutrophils and monocytes into the peripheral blood were assessed, Granulocytopoiesis was stimulated similarly by both S D/01 and G-CSF in both normal and neutropenic animals, with counts rising t o > 20 x 10(9) polymorphonuclear neutrophils/l in both cases. Bone marrow t hymidine labeling indices were increased, indicating a greater proportion o f cells in DNA synthesis and an elevated proliferative activity, Compared w ith the normally slow release of neutrophils into the peripheral blood, lab eled neutrophils (and monocytes) were rapidly released, increasing to peak levels at similar to 24 h. The peripheral half-life of neutrophils was not significantly different from normal, and the mitotic amplification factors for increase in granulocytopoiesis, accounted for by 3-3.9 extra cell divis ions, were comparable for both factors. We conclude that neutrophil kinetic s are stimulated in the same way and to the same extent by both SD/01 and G -CSF.