[Dihydropyrimidine deshydrogenase (DPD): rhythm and consequences].

Area of Science:

• Pharmacology
• Biochemistry
• Oncology

Context:

• Dihydropyrimidine dehydrogenase (DPD) is crucial for 5-fluorouracil (5-FU) metabolism.
• DPD activity deficiency is linked to increased 5-FU toxicity.
• Circadian variations in drug metabolism enzymes, including DPD, are increasingly recognized.

Purpose:

• To investigate the role of circadian variations in DPD activity in relation to 5-FU toxicity.
• To explore the potential of chronomodulated chemotherapy to mitigate 5-FU-related toxicities.
• To address the controversy surrounding the timing of individual peak DPD activity.

Summary:

• DPD is the rate-limiting enzyme in 5-FU catabolism, and its activity is typically measured in peripheral blood mononuclear cells.
• Studies suggest a link between 5-FU toxicities and DPD deficiency.
• Circadian variations in DPD activity have been observed, though peak times differ.
• Chronomodulated 5-FU-folinic acid therapy, with maximal delivery at night, significantly reduced toxicity compared to flat therapy.
• Despite improvements, 30% of patients still experience toxicities with optimized chronotherapy.

Impact:

• Chronomodulated chemotherapy can significantly reduce 5-FU toxicity, improving patient outcomes.
• Understanding individual DPD activity timing is essential for further optimizing chronotherapy.
• This research highlights the importance of considering circadian rhythms in cancer drug administration.
• Further investigation into individual DPD peak activity timing may lead to more personalized and effective cancer treatments.