Diurnal variation of cisplatin-induced anti-tumor effect and renal toxicity in mice bearing human colon cancer cells.

BACKGROUND: Cisplatin is a platinum-containing drug widely used to treat various types of cancer, which causes severe side effects, including acute renal toxicity. We previously reported that cisplatin-induced renal toxicity varies with exposure time. Administration timing may impact anticancer drug therapeutic efficacy. Although chronobiology-based approaches have been developed in both pharmacology and toxicology, reports evaluating their efficacy remain sparse. We herein investigated whether diurnal variations in cisplatin-induced anticancer effects and nephrotoxicity exhibit parallel patterns in a xenograft mouse model bearing red-fluorescent human colon cancer cells (HT29-RFP). METHODS: Using a xenograft mouse model bearing HT29-RFP cells, we compared the pharmacological and toxicological effects of cisplatin injection (5 mg/kg, intraperitoneally three times per week) in the dark (zeitgeber time (ZT) 14) or light (ZT2) phase from 2 to 6 weeks. RESULTS: Cisplatin injection during the dark phase (ZT14) resulted in stronger toxicity, including body weight reduction, and elevated plasma dysfunction and acute renal injury markers, compared to light phase (ZT2) administration. We also demonstrated that the anti-cancer potency of cisplatin against HT29-RFP cells was significantly higher with administration at ZT14 than at ZT2. CONCLUSION: These findings suggest that observed cisplatin-induced diurnal variations in toxicological and pharmacological effects follow a similar pattern in a xenograft mouse model bearing HT29-RFP cells.