Schedule-Dependent Toxicity of Tumor Necrosis Factor in Rodents

The effect of recombinant human tumor necrosis factor-alpha (rhTNF-alpha) on rodent hematopoietic precursors and hepatocytes was evaluated. rhTNF-alpha appears to have minimal toxic effects on isolated hepatocytes and on granulocyte-macrophage colony-forming units (CFU-GM) in vitro. It does, however, show a dose- and schedule-dependent inhibition of pluripotent bone marrow stem cells in mice. This was most evident with prolonged continuous infusion schedules. In contrast, single daily injections of rhTNF-alpha did not depress bone marrow or peripheral blood counts, although slight elevations in hepatic enzyme levels were apparent. These studies suggest that continuous infusions of rhTNF-alpha in man may produce enhanced bone marrow suppression over equivalent bolus doses.