Therapeutic implications of circadian rhythms in cancer patients

Drug absorption, transport, metabolism and/or elimination usually show 24 h changes in both laboratory rodents and human beings. These variations in target cell exposure to drugs, as well as the rhythms which modulate cellular detoxification functions, account for the chronopharmacology of most medications, including anticancer agents, and have warranted the exploration of the relevance of the chronotherapy principle. Most of the cellular detoxication rhythms appear to be coupled to the rest-activity cycle, both in nocturnally active rodents and in diurnally active healthy subjects as well as in cancer patients. For instance, a 24 h rhythm was found in the activity of dehydropyrimidine dehydrogenase (DPD), both in rodent liver and in human circulating mononuclear cells, with a maximum located in the early rest span in either species. This cellular enzyme catabolizes 5-fluorouracil (5-FU), hence protects normal cells against damage produced by this widely used antimetabolite drug. Although DPD amplitude was nearly threefold in rodent liver and 40% in human lymphocytes, the adaptation of 5-FU administration to this rhythm largely improved tolerability both in rodents and in patients. The results thus support the coupling of the DPD rhythm and other chronopharmacology mechanisms to the average rest-activity cycle across species. The clinical relevance of such group chronotherapy has been further validated in Phase I, II and III clinical trials involving nearly 1500 patients. Multicentre randomized clinical trials have demonstrated that chronotherapy was both better tolerated and more effective than constant rate infusion in patients with metastatic colorectal cancer. Nevertheless 24 h rhythms in plasma cortisol or rest-activity could be altered in nearly 30% of cancer patients. Results from a prospective study performed in 200 patients with metastatic colorectal cancer indicated that poor circadian coordination constitutes an independent prognostic factor of both treatment tolerability and efficacy. Novel chronotherapeutic approaches targeted at circadian system coordination should then be devised in these patients.