HUMAN GM-CSF INVIVO - IDENTIFICATION OF THE TARGET-CELLS AND OF THEIR KINETICS OF RESPONSE

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was given for three days (8 m̈g/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. Copyright © 1990 AlphaMed Press