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 murin e model to show that recombinant human interferon-alpha A/D (rHuIFN-al phaA/D) exhibited a differential potency in its peripheral white blood cell (WBC)-suppressive and bone marrow-suppressive activities accordi ng to the time in the circadian cycle at which it was administered. It was of interest to determine whether another biological response modi fier such as IFN-gamma would also exhibit a differential potency durin g 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 suppressi on and was evaluated for its ability to induce peripheral WBC suppress ion as a function of the time of rMuIFN-gamma administration. Mice wer e maintained on cycles of 12 h of light and 12 h of darkness. The rMuI FN-gamma was administered at various hours after light onset (HALO). T he rMuIFN-gamma-induced peripheral WBC-suppressive effect varied in it s 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 tre ated at 14 HALO were found to be about 20-fold less sensitive to the p eripheral WBC-suppressive effects of rMuIFN-gamma than mice treated at 4 HALO. This differential sensitivity to the peripheral WBC-suppressi ve effects of rMuIFN-gamma was examined at six different times in the circadian cycle and was found to be a general effect, occurring throug hout the circadian cycle. Using a granulocyte-macrophage colony-formin g unit (GM-CFU) assay, bone marrow function was also shown to be diffe rentially affected by treatment with rMuIFN-gamma at 4 HALO and 14 HAL O in a manner parallel to that seen with peripheral WBCs. Thus, rMuIFN -gamma exerts a differential effect on peripheral WBC counts and on bo ne marrow function according to the time in the circadian cycle at whi ch it is administered to the mouse. However, the time of maximum and m inimum effects of rMuIFN-gamma differed from those observed for rHuIFN -alphaA/D. The observed temporal variations in the myelosuppressive ac tivity of the interferons may have clinical relevance because they sug gest that a negative side-effect of IFN treatment may be moderated by the precisely timed administration of the IFNs.