CHRONOTHERAPY OF CANCER - A MAJOR DRUG-DELIVERY CHALLENGE

The evolution of life took place in a milieu influenced by cyclic interactions of the sun, earth and moon. The existence of rhythmic changes in living organisms is a sign of their adaptation to these relationships and serves as indirect evidence for time-dependent variability of the response of the human body to many drugs, including those used in the therapy of cancer. This latter possibility has been confirmed for several classical chemotherapeutics in both murine and human trials. Doxorubicin and cisplatin as well as their analogs, 5-fluorouracil and 5-fluoro-2'-deoxyuridine, have been studied in the context of their circadian pharmacodynamics and toxicology. The outcomes of these studies clearly show that proper timing of their administration reduces drug toxicity and allows for substantial increases in the maximally tolerated dose, which results in better treatment efficacy and greater comfort for patients. Also, the first steps in investigation of optimal timing and scheduling of therapeutic peptides and polypeptides (EPO, TNF, interleukin-2) have been made. Preliminary results suggest that these 'natural drugs' may be considerably more circadian time-sensitive than are classical chemotherapeutic agents. The world of chronobiology provides a new dimension for drug delivery. Multi-agent therapies, where each drug will be given in a time-dependent manner, will require sophisticated computerized multiple reservoir drug delivery systems. Closed-loop, implantable devices that stipulate optimal timing according to measures of internal circadian timing are under development. Such systems will permit cancer patients to become more active and productive. Finally, the adoption of such high-tech drug-delivery instruments will enable attention to be given to answering important chronobiologic questions and so will help to turn the science of chronobiology into what it truly is: a multidimensional and dynamic perspective on life and science.