Circadian Physiology Is a Toxicity Target of the Anticancer Drug Gemcitabine in Mice

Abstract

The circadian timing system determines the optimal timing and waveform of drug tolerability, yet treatment itself can alter this system. Gemcitabine is an antimetabolite agent that is active against lung and pancreatic cancers. Tolerability for this drug is best following dosing at ZT 11 in mice. The authors investigated the effects of gemcitabine on the circadian rhythms in body temperature and rest activity as physiological markers of the circadian timing system. Healthy unrestrained B6D2F(1) mice implanted with radiotelemetry transmitters were kept in LD 12:12 prior to receiving a single intravenous dose of gemcitabine (200, 400, or 600 mg/kg) at ZT 11 or 23. Gemcitabine (400 mg/kg) transiently suppressed the body temperature rhythm in 50% of the mice dosed at ZT 23, as compared to none of the mice treated at ZT 11 within the 2 days following drug dosing (Fisher 's exact test p = 0.04). The rest-activity circadian rhythm was suppressed in 40% (ZT 11) and 50% (ZT 23) of the mice, respectively. In the mice with persistent circadian rhythms, gemcitabine delivery at ZT 23 resulted in more prominent decreases and slower recovery of circadian mesor and amplitude of both rhythms as compared to mice treated at ZT 11. Gemcitabine also induced a transient internal desynchronization between temperature and activity rhythms following dosing at ZT 23 but not at ZT 11. The delivery of a single therapeutic dose of gemcitabine near its time of least toxicity produced least alterations in circadian physiological outputs, a finding that suggests that the extent of circadian disruption contributes to toxicokinetic processes.