Abstract
Cisplatin is one of the most commonly used chemotherapeutic drugs; however, toxicity and tumor resistance limit its use. Studies using murine models and human subjects have shown that the time of day of cisplatin treatment influences renal and blood toxicities. We hypothesized that the mechanisms responsible for these outcomes are driven by the circadian clock. We conducted experiments using wild-type and circadian disrupted Per1/2−/− mice treated with cisplatin at selected morning (AM) and evening (PM) times. Wild-type mice treated in the evening showed an enhanced rate of removal of cisplatin-DNA adducts and less toxicity than the morning-treated mice. This temporal variation in toxicity was lost in the Per1/2−/− clock-disrupted mice, suggesting that the time-of-day effect is linked to the circadian clock. Observations in blood cells from humans subjected to simulated day and night shift schedules corroborated this view. Per1/2−/− mice also exhibited a more robust immune response and slower tumor growth rate, indicating that the circadian clock also influences the immune response to melanoma tumors. Our findings indicate that cisplatin chronopharmacology involves the circadian clock control of DNA repair as well as immune responses, and thus affects both cisplatin toxicity and tumor growth. This has important implications for chronochemotherapy in cancer patients, and also suggests that influencing the circadian clock (e.g., through bright light treatment) may be explored as a tool to improve patient outcomes.
Highlights
Cisplatin is one of the most commonly used chemotherapeutic agents for the treatment of a variety of cancers, including testicular, lung, bladder, cervical, and ovarian [1]
Given that nephrotoxicity is the major side effect associated with cisplatin treatment, we measured the accumulation of cisplatin-DNA adducts (Pt-(GpG)) in vivo in kidney, liver, testis, and brain tissues of mice treated with cisplatin for 2 hours (Supplementary Figure 1A)
We treated two groups of mice with a single 2.5 mg/kg dose of cisplatin at Zeitgeber Time (ZT) 0 (ZT0 is the time www.impactjournals.com/oncotarget of lights on), which corresponds to an early morning hour (7 at selected morning (AM)), or ZT12, which corresponds to an early evening hour (7 PM)
Summary
Cisplatin (cis-Diamminedichloridoplatinum) is one of the most commonly used chemotherapeutic agents for the treatment of a variety of cancers, including testicular, lung, bladder, cervical, and ovarian [1]. According to ClinicalTrials.gov, there are over 1,000 active clinical trials involving cisplatin for the treatment of various cancer types, including melanoma [4]. The general cisplatin treatment regimen involves intravenous injection of 50-120 mg/m2 of body surface area every 3-4 weeks [5]. While experimental and clinical efforts have been made to optimize this mechanism to fight tumors, there are two major limitations to the use of cisplatin: tumor resistance and toxicity, including nephrotoxicity, ototoxicity, and leucopenia [3]
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