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Chronotherapy of cancer: biological basis and clinical application
1Laboratoire Rythmes Biologiques et Chronothérapeutique, ICIG, Université Paris XI, Hôpital P. Brousse, Villejuif, France.
Abstract:
Chronotherapy-administration of drugs according to biological rhythms-has recently followed a development similar to that of new drugs. Clinical phase I, II and III trials could reliabily be performed thanks to the avialability of specific tools for chronotherapy, e.g. programmable-in-time-pumps. In standardized and selected mice or rats, the toxicity of approximately 30 anticancer agents (anthracylines, Pt complexes, fluoropyrimidines, nitrosoureas, as well as TNF, IL-2 ...) varied 2 to 10 fold according to drug dosing time along the 24 h time scale, as a result of endogenous circadian rhythms. Dosing-time dependent changes in pharmacokinetics or tissue uptake of drug do not suffice to explain 24 hr rhythms in drug pharmacodynamic effects. Thus, cellular rhythms in target tissues, including enzymatic activities, reduced glutathione, cell division cycle, ... appear as the major mechanisms of rhythms in the cytotoxicity of cytostatic compounds. These "peripheral" mechanisms are coordinated or reset by central biological clocks. In cancer patients, the continuous infusion of 5-fluorouracil, adriamycin or vindesine at a constant rate resulted in large 24-hr changes in plasma drug levels. Mechanisms involve circadian changes in drug metabolism (e.g., dehydropyrimidine dehydrogenase for 5-FU), disposition (blood flow) or excretion (urine output). Extrapolation of times of least toxicity from nocturnally-active rodents to diurnally-active patients has been attempted through referring them to the sleep-wakefulness cycle of the considered species. Chronotherapy has allowed to significantly decrease drug toxicity and/or increase dose intensity of adriamycin, fluorouracil, FUdR, oxaliplatin and alpha-interferon.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Chronotherapy, administering drugs based on biological rhythms, significantly reduces anticancer drug toxicity. Timing drug delivery according to circadian rhythms optimizes treatment efficacy and patient outcomes.
Area of Science:
- Chronobiology
- Pharmacology
- Oncology
Background:
- Chronotherapy involves administering drugs according to biological rhythms.
- Advancements in programmable drug delivery systems enable clinical chronotherapy trials.
- Circadian rhythms influence drug efficacy and toxicity.
Purpose of the Study:
- To investigate the impact of drug administration timing on anticancer agent toxicity and efficacy.
- To explore the mechanisms underlying circadian-dependent drug effects.
- To evaluate the clinical application of chronotherapy in cancer treatment.
Main Methods:
- Toxicity studies of approximately 30 anticancer agents in rodents at different dosing times.
- Analysis of pharmacokinetic and pharmacodynamic parameters in relation to circadian rhythms.
- Clinical trials involving continuous infusion of chemotherapy in cancer patients.
- Extrapolation of optimal dosing times from animal models to human patients based on sleep-wake cycles.
Main Results:
- Drug toxicity varied 2- to 10-fold based on administration time, influenced by endogenous circadian rhythms.
- Cellular rhythms in target tissues, not just pharmacokinetics, are key to cytotoxicity rhythms.
- Circadian variations in drug metabolism, disposition, and excretion affect plasma drug levels in patients.
- Chronotherapy demonstrated significant reductions in toxicity and/or increased dose intensity for several anticancer agents.
Conclusions:
- Chronotherapy, by aligning drug administration with biological rhythms, offers a promising approach to cancer treatment.
- Circadian rhythms play a crucial role in modulating the efficacy and toxicity of anticancer drugs.
- Understanding and applying chronobiology principles can optimize chemotherapy regimens, improving patient outcomes.