CELL CYCLE-DEPENDENT CHRONOTOXICITY OF IRINOTECAN HYDROCHLORIDE IN MICE

The mechanisms underlying the circadian rhythm of the toxicity induced by irinotecan hydrochloride (CPT-11; -piperidino)-1-piperidino]carbon yloxycamptothecin) were investigated from the viewpoint of the sensiti vity of living organisms and the pharmacokinetics of the drug, ICR mal e mice were housed under standardized light-dark cycle conditions (lig hts 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-ll-induced leukopenia was m ore serious in the late dark and milder in the late light. The lower t oxicity of CPT-11 was observed when DNA synthesis and type I DNA topoi somerase activity in bone marrow cells decreased and the higher toxici ty was observed when these activities began to increase. There were ci rcadian stage-dependent changes in the concentrations of CPT-11 and it s 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-Il-induced toxicity increased. The present study suggests that the toxicity of CPT-11 is influenced by circadian rhyth m-dependent processes.