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.
Takane
H
H
Department of Clinical Pharmacokinetics, Division of Pharmaceutical Sciences, Graduate School, Kyushu University, Fukuoka, Japan.
Ohdo
S
S
Yamada
T
T
Yukawa
E
E
Higuchi
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002940:Circadian Rhythm / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta