[Chronopharmacology and chronotherapy of cancers]

Abstract

Tolerability of approximately 30 anticancer drugs vary by 50% or more according to circadian rhythms in mice or rats. Despite pharmacokinetics parameters of cytostatic drugs vary according to dosing time in rodents, cellular rhythms appear as the main mechanisms of their chronopharmacology: circadian changes in enzymatic activities involved into fluoropyrimidine (5-fluorouracil-5-FU, or floxuridine-FUdR) catabolism (dehydropyrimidine dehydrogenase) or anabolism (thymidine kinase), rhythms in reduced glutathione, involved into cellular protection against cytotoxic effects of alkylating drugs, platinum complexes and anthracyclines, rhythms in cellular proliferation of rapidly renewing tissues, such as bone marrow or intestinal tract. Furthermore, chemotherapy injection at the least toxic time allows to increase its antitumor efficacy against several transplanted rodent tumor models. Extrapolation of these results for improving therapeutic index of chemotherapy in cancer patients was based upon the hypothesis that rhythms in metabolism or proliferation of healthy tissues were tightly coupled to the circadian sleep-wakefulness cycle, both in rodents and in man. Programmable-in-time pumps allowed to test the clinical relevance of chronotherapy principle in patients with cancer metastases. Phase I clinical trials with 5-FU, FUdR, oxaliplatin-L-OHP, interferon-alpha and doxorubicin suggested that circadian-based chronomodulation of chemotherapy delivery rate both improved drug tolerability and allowed to increase its safe dose. Antitumor activity of such chronomodulated regimens, usually involving several drugs, appeared as superior to that achieved by standard protocols in Phase II clinical trials, especially in patients with renal cell cancer receiving FUdR and in patients with colorectal cancer treated with 5-FU, folinic acid (FA) and L-OHP (so called chrono-FFL regimen). A randomized european multicenter trial validated the clinical relevance of the chronotherapy principle in 278 patients with metastatic colorectal cancer: chrono-FFL was compared to flat FFL infusion and resulted in 2 to 10 times fewer severe toxic effects and a near-doubling of its antitumor efficacy, objective response rate being 51% with chrono-FFL and 30% with flat FFL (p < 0.001). These results have warranted to test further the relevance of chronotherapy in patients with breast, lung or pancreatic cancer metastases and to develop basic research on the role of biological rhythms upon cancer processes.