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-alphaA/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. Using a granulocyte-macrophage colony-forming unit (GM-CFU) assay, bone marrow function was also shown to be differentially affected by treatment with rMuIFN-gamma at 4 HALO and 14 HALO in a manner parallel to that seen with peripheral WBCs. Thus, rMuIFN-gamma exerts a differential effect on peripheral WBC counts and on bone marrow function according to the time in the circadian cycle at which it is administered to the mouse. However, the time of maximum and minimum effects of rMuIFN-gamma differed from those observed for rHuIFN-alphaA/D. The observed temporal variations in the myelosuppressive activity of the interferons may have clinical relevance because they suggest that a negative side-effect of IFN treatment may be moderated by the precisely timed administration of the IFNs.