Schedule-Dependent Toxicity of Tumor Necrosis Factor in Rodents

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Abstract
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.