Aligning chemotherapy administration to the time of day when the body is most awake benefits the effectiveness of the treatment, as shown in a mouse model. Administration of the commonly used drug, cisplatin, was optimal at the time of day when drug transporters were expressed on kidneys of the mice.1
The circadian clock affects whether a body is awake or asleep. It entrains the body to daytime and nighttime so organs and tissues can adjust their physiology appropriately. These rhythms can also affect signaling pathways involved in medication toxicity.
“The circadian clock regulates certain signaling pathways that are key for minimizing drug toxicity in normal tissues and increasing anticancer therapeutic drug efficacy,” said Shobhan Gaddameedhi, PhD, College of Pharmacy, Washington State University, Pullman, Washington, and senior author of this study.
Cisplatin is toxic to kidneys, and this toxicity can limit its use as a chemotherapy medication. This study examined the expression levels of cisplatin transporter molecules and cisplatin-DNA repair activity across a 24-hour cycle in mouse kidneys and livers.
Results showed increased expression levels of genes associated with drug transport in kidney tissues in the evening hours than in the morning hours. These genes included OCT2, MRP1, and ATP7A.
“Our laboratory is interested in understanding how cancer treatment will be more effective by administering that treatment during certain cycles of circadian rhythms,” said Panshak Dakup, a graduate student in the laboratory of Gaddameedhi, and co-author of this study.
Variation in expression levels of these genes was also observed in human blood samples, though the variation was in opposite phase of the mouse studies. The opposite phase is likely due to the fact that mice are nocturnal animals, whereas humans are diurnal.
Administration of chemotherapy when a patient’s body is at high expression of drug transporters could improve the body’s ability to fend off toxicity and side effects. Additional studies are needed to determine how circadian dosing works before it could be implemented in human treatment plans.
1. Sorenseon DN, Dakup PP, Gaddameedhi S. Chronopharmacology of cisplatin: Role of the circadian rhythm in modulating the cisplatin transporters levels [published online April 2016]. FASEB J. 2016;30(1suppl):Abstr 935.1. http://www.fasebj.org/content/30/1_Supplement/935.1.abstract. Accessed June 20, 2016.