bioRxiv : the preprint server for biologySep 25, 2023

Daily rhythms in chemotherapy sensitivity in brain tumors linked to daily changes in DNA repair gene activity and control

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 25, 2026

Abstract

Morning administration of TMZ is associated with a 6-month increase in median survival for patients with methylated GBM.

GBM cells exhibit intrinsic circadian rhythms in the expression of core circadian clock genes and the DNA repair enzyme MGMT.
Daily rhythms in GBM cells affect their susceptibility to TMZ, with increased sensitivity observed at the peak of transcription.
In preclinical mouse models, morning TMZ administration decreased tumor size and increased body weight compared to evening administration.
Inhibition of MGMT activity with O-Benzylguanine eliminated the daily rhythm in sensitivity to TMZ, enhancing susceptibility at all times.

Simplified

BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O-Methylguanine-DNA Methyltransferase () activity in murine and human models of GBM. MGMT MGMT6

METHODS AND RESULTS: recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genesand, as well as in the DNA repair enzyme,. Independent measures oftranscript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak oftranscription. We found thatmorning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O-Benzylguanine abrogated the daily rhythm in sensitivity to TMZby increasing sensitivity at both the peak and trough ofexpression. In vitro Bmal1Per2MGMT MGMT Bmal1in vivo in vitro Bmal1 6

CONCLUSION: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumorexpression and minimum ofactivity. Bmal1MGMT

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Daily rhythms in chemotherapy sensitivity in brain tumors linked to daily changes in DNA repair gene activity and control

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