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 b y the time of their administration in the circadian cycle. Previous st udies also have shown that the myelotoxicity of interferons is similar ly influenced. Purpose: This study was undertaken to evaluate the anti tumor 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 a daptation to alternating cycles of 12 hours of light and 12 hours of d ark for a period of 2-3 weeks, C57BL/6 mice were inoculated with B16 m elanoma cells intraperitoneally at different hours after light onset. Exactly 24 hours after inoculation, each group received intraperitonea l injections of either recombinant human interferon alpha (rHuIFN-alph aA/D), recombinant murine IFN-gamma (rMuIFN-gamma), or interferon-carr ier solution as control (once a day for 5 days) and were monitored for the length of their survival. Results: The antitumor activity (calcul ated as percent increased life span) of both rHuIFN-alphaA/D and rMuIF N-gamma varied with the points at which they were administered in the circadian cycle. However, the points showing minimum and maximum activ ity for rHuIFN-alphaA/D (12-16 and 0-4 hours after light onset, respec tively) did not correspond with the points for the rMuIFN-gamma (0-8 a nd 16 hours after light onset, respectively). To generate maximum anti tumor 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-f old greater amounts were required at 8 than at 16 hours after light on set (dose range, 667-6000 IU/d) (P<.01). Conclusions: In the murine tu mor model, administration of rHuIFN-alphaA/D at 4 hours after light on set and rMuIFN-gamma at 16 hours after light onset may produce maximum anti-tumor activity.