Koren S, Whorton E B, Fleischmann W R
Department of Microbiology, University of Texas Medical Branch, Galveston 77555.
J Natl Cancer Inst. 1993 Dec 1;85(23):1927-32. doi: 10.1093/jnci/85.23.1927.
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.
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.
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.
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).
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.
对抗癌药物进行的时间生物学研究表明，其有效性和/或毒性在昼夜周期中给药时间的影响下会显著变化。先前的研究还表明，干扰素的骨髓毒性也受到类似影响。
本研究旨在评估干扰素在昼夜周期中特定时间点（光照和黑暗时间相等）给药时对动物的抗肿瘤活性。
采用小鼠肿瘤模型。在适应2 - 3周的12小时光照和12小时黑暗交替周期后，在光照开始后的不同时间点给C57BL/6小鼠腹腔注射B16黑色素瘤细胞。接种后24小时，每组每天腹腔注射一次重组人干扰素α（rHuIFN-α A/D）、重组鼠干扰素γ（rMuIFN-γ）或作为对照的干扰素载体溶液（连续5天），并监测其存活时间。
rHuIFN-α A/D和rMuIFN-γ的抗肿瘤活性（以寿命延长百分比计算）随其在昼夜周期中的给药时间点而变化。然而，rHuIFN-α A/D显示最低和最高活性的时间点（分别为光照开始后12 - 16小时和0 - 4小时）与rMuIFN-γ的时间点（分别为光照开始后0 - 8小时和16小时）不对应。为产生最大抗肿瘤活性，光照开始后12小时所需的rHuIFN-α A/D量比4小时时高约五倍（剂量范围，3333 - 90,000 IU/d）（P <.0001）。同样，对于rMuIFN-γ，光照开始后8小时所需的量至少比16小时时大8.5倍（剂量范围，667 - 6000 IU/d）（P <.01）。
在小鼠肿瘤模型中，光照开始后4小时给予rHuIFN-α A/D和16小时给予rMuIFN-γ可能产生最大抗肿瘤活性。
