Chronopharmacologic Effects of Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) on Hematopoiesis in Mice

Chronopharmacologic effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on circulating white blood cell and differential counts as well as bone marrow granulocyte-macrophage colony-forming units (CFU-GM) counts were investigated in B6D2F1 mice. The animals were synchronized with an alternation of 12 h of light (L) and 12 h of darkness (D) (LD 12:12) for 3 weeks prior to study, then received a daily subcutaneous injection of rhG-CSF (400 µg/kg/day) for 4 consecutive days at 3, 9, 15 or 21 h ours a fter l ight o nset (HALO). Samples were obtained on the fifth day at the same circadian stage as that of rhG-CSF injection. rhG-CSF significantly increased the 24-h mean of leukocyte, neutrophil, lymphocyte and CFU-GM counts. Maximum increase in leukocyte and neutrophil counts was observed when rhG-CSF was administered in the middle of the dark span, while maximum stimulatory effect on circulating lymphocytes or on CFU-GM counts was obtained with rhG-CSF administration near the middle of the light span. The results indicate that choosing the dosing time of this cytokine may selectively orient its pharmacologic action. Appropriate chronomodulated delivery schemes of rhG-CSF may further reduce hematological toxicity following chemotherapy.