Abstract
The mechanisms underlying the dosing time-dependent change in the antitumor effect of interferon-β (IFN-β) were investigated based on the sensitivity of tumor cells and the pharmacokinetics of the drug. Tumor-bearing mice were housed under standardized light-dark cycle conditions (lights on at 7:00 AM, off at 7:00 PM) with food and water available ad libitum. The antitumor effect of IFN-β (0.5 MI.U./kg, intratumoral) was more efficient in early light phase than in early dark phase. The higher antitumor effect of IFN-β was observed when specific binding of IFN receptor and DNA synthesis in tumor cells increased, and the lower effect was observed when these levels decreased. The dosing time-dependent effect of IFN-β was supported by the time-dependent expression of transcription factor (signal transducers and activators of transcription 1) and cell proliferation inhibitor (p21 wild-type p53-activated fragment 1) protein induced by IFN-β. There was a significant dosing time-dependent change in IFN-β concentration in tumor, with a higher level in early light phase and a lower level in early dark phase. The dosing time-dependent change of IFN-β concentration in tumor was associated with that of IFN-β-induced antitumor effect. These results suggest that by choosing the most suitable dosing time for IFN-β, the efficacy of the drug can be increased in certain experimental and clinical situations.
Footnotes
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Send reprint requests to: Shigehiro Ohdo, Ph.D., Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582 Japan. E-mail:ohdo{at}shunsan.phar.kyushu-u.ac.jp
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↵1 This research was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture, Japan (to S.O., 00223884).
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Received for publication January 19, 2000.
- Abbreviations:
- IFN
- interferon
- STAT
- signal transducers and activators of transcription
- p21WAF1
- p21 wild-type p53-activated fragment
- cdk
- cyclin-dependent kinase
- NONMEM
- nonlinear mixed effect model
- CL
- clearance
- Vc
- central volume of distribution
- k12
- distribution rate constant from central to peripheral compartment
- k21
- distribution rate constant from peripheral to central compartment
- AUC
- area under the curve
- MRT
- mean residence time
- Accepted April 25, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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