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Time of Day Influences Inflammatory Response to Cytotoxic Chemotherapy

 

 

It has been demonstrated cancer chemotherapy depends on administration of treatment at times that coincide with both optimal drug metabolism and cellular processes such as apoptosis, DNA repair and changes to cell cycle progression. Given we know immune response is also strongly influenced by circadian cycles, it seems reasonable to consider the possibility that the daily cycles of cytokines and immune response proteins may also contribute to the effectiveness of chemotherapeutics.  Borniger et al. (Science Reports, 2017) investigated this correlation in ovariectomized mice who received either 13.5 mg/ml doxorubicin + 135 mg/kg cyclophosphamide or saline vehicle by IV.  The mice were maintained on a 12:12 light dark cycle and were divided into groups treated at ZT2 (two hours after lights on) or ZT14 (two hours after lights off).  1, 3, 9 and 24 hours after injection mice were sacrificed and tissues collected to assess cytokine and chemokine circulating concentrations (in serum), cytokine transcription via RT-qPCR (in spleen, liver and brain samples) and corticosterone levels in serum (via Arbor Assays DetectX Corticosterone EIA kit, cat. K014-H).

The Borniger study showed mice injected at ZT2 showed elevated cytokine response in the spleen to the chemotherapy injections as compared to those injected at ZT14 for IL-1β, TNF-α, SOCS3, IL-1ra and iNOS, but not for IL-6 or MAC-1.  Central cytokine transcription as measured in the hypothalamus showed interaction between injection time and treatment for IL3β, TNF-α, CCL2, SOCS3, and STAT3 such that animals injected at T14 had elevated response to chemotherapy injection over mice injected at T2 (a nearly opposite response from what was observed in spleen).

Corticosterone levels were altered by the injection alone (elevated at ZT14 vs ZT2 in mice treated with just the saline vehicle).  However the chemotherapy treatment increased circulating corticosterone (relative to mice treated with the vehicle alone) in mice injected at ZT2 and not in mice injected at ZT14, suggesting injection time does have differential effects on glucocorticoid response to the chemotherapy drugs

The transcription levels of enzymes involved in Cyclo/DOX metabolism were examined in the liver samples to determine if time of injection may influence drug metabolism.  Chemotherapy significantly increased expression of Cyp2b10, Cyp3a13 and Cbr1 in the liver as compared to injection of vehicle alone.   There was also a correlation between treatment and injection time for Cyp2b10 absent for the other two liver enzymes studied.   Activity of Cyp2b10 positively correlated with the expression of many proinflammatory cytokines in the spleen of mice that were injected at ZT2

Finally circulating cytokine levels were measured in serum.  Borniger reported an increase in circulating levels of IL-6 in serum in chemo-treated mice over mice treated with vehicle, but not for any of the other measured cytokines.  There was no interaction found between injection time and treatment in any of the serum proteins studied.

Taken all together these data indicate tissue specific time-of-day dependent changes in inflammatory response to chemotherapy.   These changes will influence both the effectiveness and tolerance for the drugs in human patients (although diurnal humans typically have opposing responses to nocturnal rodents).  It’s clearly important to provide chemotherapy treatments on a time schedule optimized for maximum effectiveness and tolerance wherever possible.

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