Sex and Dosing-Time Dependencies in Irinotecan-Induced Circadian Disruption

Abstract

Circadian disruption accelerates malignant growth; thus, it should be avoided in anticancer therapy. The circadian disruptive effects of irinotecan, a topoisomerase I inhibitor, was investigated according to dosing time and sex. In previous work, irinotecan achieved best tolerability following dosing at zeitgeber time (ZT) 11 in male and ZT15 in female mice, whereas worst toxicity corresponded to treatment at ZT23 and ZT3 in male and female mice, respectively. Here, irinotecan (50 mg/kg intravenous [i.v.]) was delivered at the sex-specific optimal or worst circadian timing in male and female B6D2F1 mice. Circadian disruption was assessed with rest-activity, body temperature, plasma corticosterone, and liver mRNA expressions of clock genes Rev-erbα, Per2, and Bmal1. Baseline circadian rhythms in rest-activity, body temperature, and plasma corticosterone were more prominent in females as compared to males. Severe circadian disruption was documented for all physiology and molecular clock endpoints in female mice treated at the ZT of worst tolerability. Conversely, irinotecan administration at the ZT of best tolerability induced slight alteration of circadian physiology and clock-gene expression patterns in female mice. In male mice, irinotecan produced moderate alterations of circadian physiology and clock-gene expression patterns, irrespective of treatment ZT. However, the average expression of Rev-erbα, Per2, and Bmal1 were down-regulated 2- to 10-fold with irinotecan at the worst ZT, while being minimally or unaffected at the best ZT, irrespective of sex. Corticosterone secretion increased acutely within 2 h with a sex-specific response pattern, resulting in a ZT-dependent phase-advance or -delay in both sex. The mRNA expressions of irinotecan clock-controlled metabolism genes Ce2, Ugt1a1, and Top1 were unchanged or down-regulated according to irinotecan timing and sex. This study shows that the circadian timing system represents an important toxicity target of irinotecan in female mice, where circadian disruption persists after wrongly timed treatment. As a result, the mechanisms underling cancer chronotherapeutics are expectedly more susceptible to disruption in females as compared to males. Thus, the optimal circadian timing of chemotherapy requires precise determination according to sex, and should involve the noninvasive monitoring of circadian biomarkers.

Thoracic surface temperature rhythms as circadian biomarkers for cancer chronotherapy

“…In contrast, CTS re-enforcement with meal timing, a potent synchronizer of peripheral clocks, nearly halves experimental tumor growth (Filipski et al, 2005; Li et al, 2010; Wu et al, 2004). Anticancer drugs can also disrupt both circadian activity and temperature patterns, as well as molecular clocks, as a function of dose and circadian timing in mice (Ahowesso et al, 2011; Lévi et al, 2010; Li et al, 2002; Ohdo et al, 2001). Thus, the temperature circadian rhythm appears both as a biomarker of CTS function and as an endogenous synchronizer of peripheral clocks.…”

Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling

“…Irinotecan efficacy and toxicity displayed circadian rhythms in groups of mice and patients (2,17). Several genes and proteins involved in irinotecan PK and/or PD display circadian rhythms in mouse liver and/or intestine, including the drug target Top1 (18), the bioactivation enzymes Ces1 and Ces2 (19), the detoxification enzyme Ugt1a1 (19), and the efflux transporters Abcb1a, Abcb1b, and Abcc2 (17,18,(20)(21)(22). Studies in 8 mouse categories, based on differences in sex and genetic background, revealed large differences in irinotecan chronopharmacology.…”

Relevance of a Mobile Internet Platform for Capturing Inter- and Intrasubject Variabilities in Circadian Coordination During Daily Routine: Pilot Study (Preprint)

“…Two separate clinical trials uncovered that the optimal timing of a multidrug chronomodulated chemotherapy protocol could lag 6 h behind in women as compared to men with this same cancer type [63,64]. Such differences in circadian amplitudes, and time lag between males and females were similar in cancer patients and in mouse models [65,66]. The sex-related differences in circadian timing system that were discovered here could explain why the same multidrug cancer chronotherapy protocol improved response rate, progression-free survival and overall survival in men, but not in women with metastatic colorectal cancer, independently of all other prognostic factors within a meta-analysis of three randomized international clinical trials involving 842 patients [28].…”