Chronopharmacology of Melatonin in Mice to Maximize the Antitumor Effect and Minimize the Rhythm Disturbance Effect

Takanori Akagi, Kazami Ushinohama, Shoko Ikesue, Eiji Yukawa, Shun Higuchi, Kenji Hamase, Kiyoshi Zaitsu, Shigehiro Ohdo

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

The influence of dosing time on the antitumor effect and the rhythm disturbance effect of melatonin (MLT) was investigated in ICR male mice under a light/dark (12:12) cycle. In tumor-bearing mice, the antitumor effect of MLT (1 mg/kg intraperitoneal) was most effective in the dark phase; and the rhythm disturbance effect of MLT on the locomotor activity was more serious in the light phase than in the dark phase. The antitumor effect and the rhythm disturbance effect of MLT increased when the specific binding of MLT receptor in target tissues, tumor or suprachiasmatic nucleus, increased and they decreased when the level decreased. Furthermore, because luzindole, an MT 1 and MT2 blocker, caused the antitumor effect or rhythm disturbance effect of MLT to decrease, it is suggested that the time-dependent change of the pharmacological effects of MLT were influenced by that of MLT receptor(s) function. On the other hand, there was no significant dosing time-dependent change of MLT concentration in tumor or brain after injection. Thus, the pharmacokinetic factor does not seem to contribute to the dosing time-dependent effect of MLT. These results suggest that by choosing the most suitable dosing time for MLT, the efficacy of the drug can be increased, and the toxicity of the drug can be decreased in certain experimental and clinical situations.

Original languageEnglish
Pages (from-to)378-384
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume308
Issue number1
DOIs
Publication statusPublished - Jan 2004

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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