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Protective Effects of Tumor Necrosis Factor on Murine Hematopoiesis during Cycle-specific Cytotoxic Chemotherapy¹

The James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Tumor necrosis factor (TNF) is a pleiotropic cytokine which exerts a wide range of effects when administered in vivo. Using a murine model, we have investigated the effect of pretreatment with 1 µg (2.6 x 10⁴ units) per mouse of recombinant murine TNF- on hematopoietic recovery following administration of cyclophosphamide, 5-fluorouracil, methotrexate, or vinblastine. TNF pretreatment results in enhanced regeneration of circulating neutrophils and hematopoietic progenitors, as measured by in vivo and in vitro assays, in animals given cycle-specific chemotherapeutic agents. The results may suggest that TNF affects cycle kinetics in hematopoietic progenitor cell populations, thus making these cells less prone to the cytocidal effects of the chemotherapeutic agents. As myeloablation is a frequent and often critical side effect following cancer treatment, these findings may have clinical implications.

¹ This work was supported by USPHS Grants CA032516, CA-20194, and CA-23766 from the National Cancer Institute; American Cancer Society Grant CA-3K; and the Gar Reichman Fund of the Cancer Research Institute. D. J. W. is supported by a fellowship of the Leukemia Society of America.

² Fellow of the Norwegian Cancer Society. To whom requests for reprints should be addressed, at the Clinical Pharmacology Unit, Department of Pharmacology and Toxicology, University of Bergen, N-5021 Bergen, Norway.

Received 12/ 7/89. Revised 3/12/90.

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