Chronopharmacology of antitumor effect induced by interferon-beta in tumor-bearing mice

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