EFFECT OF PLASMA TNF-ALPHA ON FILGRASTIM-STIMULATED HEMATOPOIESIS IN MICE AND HUMANS

Study Objective. To delineate possible explanations for a nonmonotone hematopoiesis, dose-response curve with filgrastim therapy after high- dose chemotherapy. Design. Sequential two-phase study. Settings. Unive rsity teaching hospital and basic pharmaceutical sciences laboratory. Subjects. Thirty-nine patients with breast cancer or melanoma and 15 n ormal CF-1 male mice. Interventions. Serial blood samples were obtaine d from patients after high-dose chemotherapy to evaluate hematopoiesis and tumor necrosis factor-alpha (TNF-alpha) concentrations. Murine he matopoiesis was induced by filgrastim with or without coadministration of lipopolysaccharide. Measurements and Main Results. Detection of pl asma TNF-alpha in patients corresponded to substantially slower recove ry of granulocytes, erythrocytes, and platelets, and was directly prop ortional to the prescribed dosage of filgrastim. Lipopolysaccharide st imulated the secretion of TNF-alpha in mice and totally aberrated filg rastim-induced granulopoiesis. Conclusions. This in vivo evidence sugg ests that regulatory pathways involving endogenous cytokines may overr ide the effect of recombinant cytokines.