Chronotherapy of cancer: biological basis and clinical application.

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)