报告人：Albert Goldbeter（Université Libre de Bruxelles (ULB), Brussels, Belgium）
时间：8.31， 15：00-16：00
地点:维格堂319
Abstract
Circadian rhythms control most aspects of human physiology, including the response to drugs. It is therefore not surprising that the effect of medications often depends on the timing of their administration. These observations led to the emergence in the last three decades of the fields of Chronopharmacolgy and Chronotherapy. Clinical applications of chronotherapy have mainly been developed for the treatment of various types of cancer. Enhancement of treatment efficacy through circadian administration of anticancer drugs is closely related to the fact that many anticancer drugs kill target cells at specific phases of the cell cycle. To assess by means of a mathematical approach the efficiency of various circadian patterns of anticancer drug delivery we thus need to model the cell cycle. To keep modeling as simple and compact as possible, we developed an automaton model for the cell cycle based on the sequential transitions between its successive phases G1, S (DNA replication), G2, and M (mitosis). The automaton model allows us to simulate the distribution of cell cycle phases as well as entrainment by the circadian clock. We use the model to evaluate circadian patterns of administration of the anticancer drug 5-fluorouracil (5-FU), which kills cells in S phase. We compare various circadian patterns of drug administration differing by the time of maximum drug delivery. The model explains why minimum cytotoxicity is obtained when the time of peak delivery is close to 4 a.m., which temporal pattern of drug administration is used clinically for 5-FU. We also determine how cytotoxicity is affected by the variability in duration of cell cycle phases and by cell cycle length in the presence or absence of entrainment by the circadian clock. The results indicate how the same temporal pattern of drug administration can have minimum cytotoxicity toward one cell population, e.g. of normal cells, and at the same time can display high cytotoxicity toward a second cell population, e.g. of tumor cells. Thus the model allows us to uncover factors that may contribute to improve simultaneously chronotolerance (minimizing damage to healthy tissue) and chronoefficacy (maximizing damage to cancer cells) of anticancer drugs.