Circadian variations in myelosuppressive activity of interferon-alpha in mice: identification of an optimal treatment time associated with reduced myelosuppressive activity.
A number of antitumor drugs have been shown to vary in their toxicity and in their antitumor potency according to the time in the circadian cycle at which they are administered. It was of interest to determine whether other agents, such as a biological response modifier, would also exhibit differential potency during the circadian cycle. Interferons (IFNs) are biological response modifiers which have antitumor and antiviral activity and which also have toxic side effects. A mouse model was used to study one of these toxic side effects, peripheral white blood cell (WBC) suppression. Interferon-induced peripheral WBC suppression was evaluated as a function of the time of recombinant human (rh) IFN-alpha A/D administration. Mice were maintained on cycles of 12 hours of light and 12 hours of darkness. The rhIFN-alpha A/D was administered at various hours after light onset (HALO). The rhIFN-alpha A/D-induced peripheral WBC suppressive effect varied in its intensity in a cyclical manner. Administration of rhIFN-alpha A/D at 0 HALO caused the greatest suppressive effect, while administration of rhIFN-alpha A/D at 8 HALO caused the least suppressive effect. Mice treated at 8 HALO were found to be about 10-fold less sensitive to the peripheral WBC suppressive effects of rhIFN-alpha A/D than mice treated at 0 HALO. This differential sensitivity to the peripheral WBC suppressive effects of rhIFN-alpha A/D was examined for 6 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 rhIFN-alpha A/D at 0 HALO and 8 HALO in a manner parallel to that seen with peripheral WBC. Thus, rhIFN-alpha A/D 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. Such temporal variation in the myelosuppressive activity of interferons could be important in designing future clinical trials with these antiviral and antitumor agents. Administration of interferons at empirically determined times in the circadian cycle could be used to reduce the myelotoxic side effects of interferons in humans.