Human GM-CSF in vivo: identification of the target cells and of their kinetics of response.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) was given for three days (8 micrograms/kg/day) to 14 subjects who had solid tumors and normal hemopoiesis. The treatment induced a rapid 3- to 5-fold increase in the number of circulating neutrophils, eosinophils and monocytes. Lymphocytes, platelets and reticulocytes were unmodified during treatment. Activation of circulating neutrophils during GM-CSF treatment was demonstrated by a significant, increased release of neutrophil-derived platelet-activating factor after stimulation with N-formyl-methionyl-leucyl-phenylalanine, tumor necrosis factor-alpha or phagocytosis. The granulomonocytosis was dependent on increased bone marrow production of mature cells. Using the thymidine suicide technique, we observed that GM-CSF more than doubled the percentage of granulocyte-macrophage and megakaryocyte colony-forming units (CFU-gm and CFU-meg) and erythroid burst-forming units (BFU-e) in the S phase of the cell cycle. However, at the level of morphologically recognizable cells with autoradiography, we observed that GM-CSF increased the labeling index of the granulo-monopoietic cells, whereas that of the erythroblasts was unchanged. These data suggest that in accordance with in vitro observations, GM-CSF exerts its activity through all granulo-monopoietic lineages, whereas other cytokines (erythropoietin, thrombopoiesis-stimulating factors) may be needed to fully exploit the proliferative stimulus of GM-CSF on BFU-e and CFU-meg. After treatment discontinuation, the proliferative activity drops to values lower than before treatment, suggesting a period of relative refractoriness of marrow progenitors to the cytocidal effect of cell cycle-specific antineoplastic agents. This hypothesis is under evaluation in a controlled clinical trial where GM-CSF is given prior to chemotherapy.
Aglietta
M
M
Clinica Medica A, Dipartimento di Scienze Biomediche ed Oncologia Umana, Italy.
Bussolino
F
F
Piacibello
W
W
Aprá
F
F
Sanavio
F
F
Stacchini
A
A
Monzeglio
C
C
Carnino
F
F
Gavosto
F
F
D016026:Bone Marrow Transplantation; D003115:Colony-Stimulating Factors / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy* / Q000628:therapy; D007958:Leukocyte Count; D009504:Neutrophils / Q000187:drug effects
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D016178:Granulocyte-Macrophage Colony-Stimulating Factor