CIRCADIAN DEPENDENCE OF INTERFERON ANTITUMOR-ACTIVITY IN MICE

Background: Chronobiological studies with anticancer drugs have shown that their effectiveness and/or toxicity is significantly influenced by the time of their administration in the circadian cycle. Previous studies also have shown that the myelotoxicity of interferons is similarly influenced. Purpose: This study was undertaken to evaluate the antitumor activity of interferons as a function of their administration to animals at defined points in the circadian cycle with equal light and dark periods. Methods: A murine tumor model was employed. Following adaptation to alternating cycles of 12 hours of light and 12 hours of dark for a period of 2-3 weeks, C57BL/6 mice were inoculated with B16 melanoma cells intraperitoneally at different hours after light onset. Exactly 24 hours after inoculation, each group received intraperitoneal injections of either recombinant human interferon alpha (rHuIFN-alphaA/D), recombinant murine IFN-gamma (rMuIFN-gamma), or interferon-carrier solution as control (once a day for 5 days) and were monitored for the length of their survival. Results: The antitumor activity (calculated as percent increased life span) of both rHuIFN-alphaA/D and rMuIFN-gamma varied with the points at which they were administered in the circadian cycle. However, the points showing minimum and maximum activity for rHuIFN-alphaA/D (12-16 and 0-4 hours after light onset, respectively) did not correspond with the points for the rMuIFN-gamma (0-8 and 16 hours after light onset, respectively). To generate maximum antitumor activity, approximately fivefold higher amounts of rHuIFN-alphaA/D were required at 12 than at 4 hours after light onset (dose range, 3333-90000 IU/d) (P<.0001). Similarly, for rMuIFN-gamma at least 8.5-fold greater amounts were required at 8 than at 16 hours after light onset (dose range, 667-6000 IU/d) (P<.01). Conclusions: In the murine tumor model, administration of rHuIFN-alphaA/D at 4 hours after light onset and rMuIFN-gamma at 16 hours after light onset may produce maximum anti-tumor activity.