Vol. 294, Issue 2, 746-752, August 2000

Chronopharmacology of Antitumor Effect Induced by Interferon- in Tumor-Bearing Mice¹

Hiroshi Takane, Shigehiro Ohdo, Tomoko Yamada, Eiji Yukawa and Shun Higuchi

Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Fukuoka, Japan

The mechanisms underlying the dosing time-dependent change in the antitumor effect of interferon- (IFN-) 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- (0.5 MI.U./kg, intratumoral) was more efficient in early light phase than in early dark phase. The higher antitumor effect of IFN- 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- 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-. There was a significant dosing time-dependent change in IFN- 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- concentration in tumor was associated with that of IFN--induced antitumor effect. These results suggest that by choosing the most suitable dosing time for IFN-, the efficacy of the drug can be increased in certain experimental and clinical situations.