Optimal circadian timing reduces the myelosuppressive activity of recombinant murine interferon-gamma administered to mice.
There is a marked, reproducible circadian variation in the toxicity of a number of antineoplastic drugs. A recent study has employed a murine model to show that recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) exhibited a differential potency in its peripheral white blood cell (WBC)-suppressive and bone marrow-suppressive activities according to the time in the circadian cycle at which it was administered. It was of interest to determine whether another biological response modifier such as IFN-gamma would also exhibit a differential potency during the circadian cycle. A mouse model was used to study peripheral WBC suppression, a toxicity associated with IFN-gamma therapy. Recombinant murine (rMu)IFN-gamma was employed to induce peripheral WBC suppression and was evaluated for its ability to induce peripheral WBC suppression as a function of the time of rMuIFN-gamma administration. Mice were maintained on cycles of 12 h of light and 12 h of darkness. The rMuIFN-gamma was administered at various hours after light onset (HALO). The rMuIFN-gamma-induced peripheral WBC-suppressive effect varied in its intensity in a cyclical manner. Administration of rMuIFN-gamma at 4 HALO caused the greatest suppressive effect, whereas administration of rMuIFN-gamma at 14 HALO caused the least suppressive effect. Mice treated at 14 HALO were found to be about 20-fold less sensitive to the peripheral WBC-suppressive effects of rMuIFN-gamma than mice treated at 4 HALO. This differential sensitivity to the peripheral WBC-suppressive effects of rMuIFN-gamma was examined at six different times in the circadian cycle and was found to be a general effect, occurring throughout the circadian cycle.(ABSTRACT TRUNCATED AT 250 WORDS)
Koren
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S
Department of Microbiology, University of Texas Medical Branch, Galveston 77550.
Fleischmann
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WR
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D007371:Interferon-gamma / Q000008:administration & dosage / Q000633:toxicity*; D007958:Leukocyte Count / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins
D011994:Recombinant Proteins; D007371:Interferon-gamma