Abstract | 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.
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Authors | S Koren, E B Whorton Jr, W R Fleischmann Jr |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 85
Issue 23
Pg. 1927-32
(Dec 01 1993)
ISSN: 0027-8874 [Print] United States |
PMID | 8230283
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Interferon Type I
- Recombinant Proteins
- Interferon-gamma
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Topics |
- Analysis of Variance
- Animals
- Circadian Rhythm
- Female
- Germ-Free Life
- Interferon Type I
(pharmacology)
- Interferon-gamma
(pharmacology)
- Melanoma, Experimental
(drug therapy)
- Mice
- Mice, Inbred C57BL
- Recombinant Proteins
- Tumor Cells, Cultured
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