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The biological clock is involved in many aspects of regulating complex physiology in all animals. It was in 1935 when German zoologists, Hans Kalmus and Erwin Bünning, discovered the existence of circadian rhythm in Drosophila melanogaster. However, the internal molecular mechanisms behind the circadian clock remained a mystery until 1984, when Jeffrey C. Hall, Michael Rosbash, and Michael W. Young discovered the expression of the Per gene oscillating over a 24-hour cycle. In subsequent...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Circadian rhythms are cyclic changes that are crucial in plasma drug concentrations. Various standard circadian parameters, including core body temperature, heart rate, and other cardiovascular factors, directly impact disease states and the therapeutic response to drug therapy.
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Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
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Chronopharmacokinetics studies the temporal change in drug absorption and elimination. These changes can be cyclical or non-cyclical. Cyclical changes occur over a regular interval, while non-cyclical changes occur over a longer, irregular period.
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Circadian clock, carcinogenesis, chronochemotherapy connections.

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Keywords:
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Area of Science:

  • Chronobiology
  • Cancer Research
  • Molecular Biology

Background:

  • The circadian clock regulates nearly 50% of genes, impacting cellular functions like cell cycle and division.
  • Disruption of circadian rhythms is linked to potential pathological effects, including cancer, but epidemiological and genetic studies show conflicting results.
  • Despite the clock's influence on cellular processes, attempts at chronochemotherapy have not yielded consistent benefits.

Purpose of the Study:

  • To investigate the impact of circadian time on DNA damage and repair following anticancer drug treatment.
  • To explore the potential for developing rational chronochemotherapy regimens based on mechanistic understanding.

Main Methods:

  • Genome-wide mapping of DNA damage and repair sites at single nucleotide resolution in mice.
  • Utilizing mice with and without human tumor xenografts.
  • Analyzing damage and repair patterns as a function of circadian time after cisplatin treatment.

Main Results:

  • Cisplatin-induced DNA damage and repair exhibit circadian rhythmicity.
  • Specific genomic sites show differential susceptibility to damage and repair based on circadian timing.
  • These findings provide a mechanistic basis for understanding drug response in relation to the circadian clock.

Conclusions:

  • Circadian timing influences the efficacy and side effects of chemotherapy by affecting DNA damage and repair.
  • Mechanism-based studies are crucial for developing effective chronochemotherapy strategies.
  • Further research can optimize cancer treatment by aligning drug administration with the body's natural rhythms.