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.
Liddil
J D
JD
Arizona Cancer Center, University of Arizona, Department of Pharmacology, Tucson 85724.
Dorr
R T
RT
D000818:Animals; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004334:Drug Administration Schedule; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000633:toxicity*
D014409:Tumor Necrosis Factor-alpha