Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice

Shigehiro Ohdo, Tomoko Makinosumi, Takashi Ishizaki, Eiji Yukawa, Shun Higuchi, Shigeyuki Nakano, Nobuya Ogawa

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

The mechanisms underlying the circadian rhythm of the toxicity induced by irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin) were investigated from the viewpoint of the sensitivity of living organisms and the pharmacokinetics of the drug. ICR male mice were housed under standardized light-dark cycle conditions (lights on at 0700, off at 1900) with food and water ad libitum. The loss of body weight after an intraperitoneal injection of CPT-11 (100 mg/kg) was more serious in the late dark and the early light and milder in the late light and the early dark. The CPT-11-induced leukopenia was more serious in the late dark and milder in the late light. The lower toxicity of CPT-11 was observed when DNA synthesis and type 1 DNA topoisomerase activity in bone marrow cells decreased and the higher toxicity was observed when these activities began to increase. There were circadian stage-dependent changes in the concentrations of CPT-11 and its major metabolite (SN-38; 7-ethyl-10-hydroxycamptothecin) in plasma. The higher concentrations of CPT-11 and SN-38 in plasma were observed when the level of CPT-11-induced toxicity increased. The present study suggests that the toxicity of CPT-11 is influenced by circadian rhythm- dependent processes.

Original languageEnglish
Pages (from-to)1383-1388
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume283
Issue number3
Publication statusPublished - Dec 1 1997

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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