The circadian timing system as a toxicity target of the anticancer mTOR inhibitor everolimus in mice


ÖZTÜRK N. , OKYAR A. , Li X., Levi F.

17th World Congress of Basic and Clinical Pharmacology (WCP2014), Cape Town, South Africa, 13 - 18 July 2014, vol.115, no.1, pp.318

  • Publication Type: Conference Paper / Full Text
  • Volume: 115
  • City: Cape Town
  • Country: South Africa
  • Page Numbers: pp.318

Abstract

Background: The adaptation of chemotherapy to circadian rhythms, termed chronotherapy, improves anticancer drug tolerability and antitumor efficacy in mammals. The circadian timing system (CTS) determines the optimal timing and 24-h waveform of drug tolerability. Yet treatment itself can alter the CTS. Everolimus is mTOR inhibitor which is active against renal and breast cancers. Our aim was to investigate the effects of everolimus on the circadian rhythms in body temperature and rest-activity as physiological biomarkers of the CTS in mice. Methods: C57BL/6J male mice were synchronized with 12 h of Light and 12 h of Dark (LD12:12, with Zeitgeber Time 0 - ZT0 - corresponding to L onset) and implanted intraperitoneally with a telemetric temperature and activity sensor. Ten days later, everolimus (5 or 10 mg/kg) or vehicle were orally administered at ZT1, ZT7, ZT13 or ZT19 daily for 14 days. Temperature and locomotor activity were automatically recorded. Results: Everolimus suppressed or altered both rest-activity and temperature rhythms as a function of dose and drug timing. Most severe alterations in all cosinor-computed rhythm parameters (24-h mean, period, amplitude, time of maximum) were found in mice dosed with 10 mg/kg at ZT1 (resting span). In contrast, circadian rhythms remained robust in those mice treated with 5 mg/kg at ZT13 (activity span). The overall toxicity of 5 mg/kg everolimus for 14 days was mild, without any mortality. Mean body weight loss was twice as large in mice on 5 mg/kg at ZT1 as compared to ZT13 (12.9% vs. 5.5%, ANOVA P < 0.001). Everolimus dose of 10 mg/kg caused lethal toxicities that varied dramatically according to drug timing, resulting in 50% mortality following dosing at ZT1 or ZT7, and no toxic death in mice treated at ZT13. Using body weight loss as an endpoint, dose and timing were found as independent critical factors for everolimus tolerability (ANOVA, P < 0.001 and P = 0.035, respectively). Conclusions: Circadian timing was a critical as dose for the determination of everolimus tolerability in mice. These findings support the concept of everolimus chronotherapy for minimizing the severe adverse events of this yet effective drug in the clinic.