Effect of Plasma TNF‐α 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. University teaching hospital and basic pharmaceutical sciences laboratory. Subjects. Thirty-nine patients with breast cancer or melanoma and 15 normal CF-1 male mice. Interventions. Serial blood samples were obtained from patients after high-dose chemotherapy to evaluate hematopoiesis and tumor necrosis factor-α (TNF-α) concentrations. Murine hematopoiesis was induced by filgrastim with or without coadministration of lipopolysaccharide. Measurements and Main Results. Detection of plasma TNF-α in patients corresponded to substantially slower recovery of granulocytes, erythrocytes, and platelets, and was directly proportional to the prescribed dosage of filgrastim. Lipopolysaccharide stimulated the secretion of TNF-α in mice and totally aberrated filgrastim-induced granulopoiesis. Conclusions. This in vivo evidence suggests that regulatory pathways involving endogenous cytokines may override the effect of recombinant cytokines.