Synergy between recombinant human IL-1 alpha (rHuIL-1) and M-CSF (rHuM-CSF) during the recovery of murine hematopoietic activity in myelosuppressed animals: abbreviated versus chronic administration of rHuM-CSF.
The ability of highly purified, recombinant human macrophage colony-stimulating factor (M-CSF) and recombinant human interleukin 1 alpha (IL-1) to rescue hematopoietic activity from the myelosuppressive effects of 5-fluorouracil (5-FU) was investigated in the C57Bl/6 mouse. IL-1 (q24 h x 4) stimulated granulopoietic recovery in the 5-FU-treated animals and reduced the period of severe neutropenia associated with this drug by 7 days. Chronic M-CSF administration (q24 h x 14), on the other hand, resulted in a modest retardation of granulocyte recovery, and, when combined with IL-1, the chronic administration of M-CSF significantly dampened the accelerated recovery of granulopoietic activity observed with IL-1 alone. Consistent with their effects on neutrophil recovery, IL-1 alone markedly enhanced the recovery of the granulocyte erythrocyte macrophage megakaryocyte colony-forming units (CFU-GEMM), macrophage colony-forming units (CFU-M), and erythroid burst-forming units (BFUe) in the marrow, whereas M-CSF failed to demonstrate a significant influence on the restoration of these hematopoietic progenitors (with the exception of delaying the recovery of the BFUe). Unexpectedly, the combination of IL-1 plus M-CSF (q24 h, days 1-4) followed by M-CSF (q24 h, days 5-14) resulted in a more than additive stimulation of progenitor recovery in both the marrow and the spleen that was observed as early as day 3 following 5-FU treatment. Furthermore, in the absence of protracted M-CSF administration on days 5-14, the 4-day rescue with a combination of IL-1 plus M-CSF also resulted in a more than additive effect on the recovery from 5-FU-induced neutropenia. Collectively, these observations demonstrated that IL-1 and M-CSF can interact synergistically to stimulate granulopoietic recovery in the 5-FU-treated animal. However, the data also suggest that the continued administration of M-CSF following the 4-day IL-1 plus M-CSF rescue may interfere with the restoration of neutrophils in the myelosuppressed animal.
Kovacs
C J
CJ
Department of Radiation Oncology, Leo Jenkins Cancer Center, East Carolina University School of Medicine, Greenville, North Carolina 27858.
Harrell
J P
JP
Gooya
J M
JM
Evans
M J
MJ
Johnke
R M
RM
D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D004357:Drug Synergism; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology
D007375:Interleukin-1; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor; D005472:Fluorouracil