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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-alpha A/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-alpha A/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-alpha A/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-alpha A/D were required at 12 than at 4 hours after light onset (dose range, 3333-90,000 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-alpha A/D at 4 hours after light onset and rMuIFN-gamma at 16 hours after light onset may produce maximum antitumor activity.

While underlying biological mechanisms responsible for sister chromatid exchange (SCE) formation are not fully understood, scientists worldwide are increasingly using SCEs in the evaluation of excess risk from exposure to chemical and biological agents. SCEs are being used as endpoint measures of cell damage in many types of experimental and nonexperimental investigations. The former includes both simple and complex randomized experiments using both animals exposed in vivo and cells exposed in vitro as experimental units. The latter includes the important, yet potentially misleading, human case-control studies in which a group of humans who are or have been exposed to some agent are compared with a selected nonexposed group on SCE frequency. As more is learned about those factors which result in SCE variations, the assay techniques and study protocols can be adjusted to enhance study sensitivity and to minimize potential bias. Although research concerning sample sizes and statistical analysis methods has been conducted, more is needed. Search for other sources of intersubject variations in SCEs should continue so that such sources can be controlled in future studies, particularly the human exposure types. A number of experimental designs are presented and contrasted with their nonexperimental counterparts. Statistical methods are summarized and sample size options are given for the human and animal exposure studies and for the studies in which cells are exposed in vitro.