A Step Toward Optimization of Cancer Therapeutics [Chronobiological Investigations]

Inst. Nat. de Recherche en Inf. et en Autom., Rocquencourt
IEEE Engineering in Medicine and Biology Magazine (Impact Factor: 2.73). 02/2008; DOI: 10.1109/MEMB.2007.907363
Source: IEEE Xplore

ABSTRACT An integrative physiology model has been designed, which takes into account the cell proliferation at the level of a population of cells by age-structured partial differential equations (PDEs), its control by cell cycle proteins, and the control of these molecular mechanisms by the circadian system, designed as a network of coupled oscillators also described by ODEs. Cancer growth and response to therapy by anticancer drugs have been shown to be dependent on circadian clock inputs. This multiscale modeling framework will provide clinicians with a theoretical tool to bridge the gap between the pharmaceutical clinical control level and the molecular pharmacological hidden level of drug action.

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    ABSTRACT: We study proliferation in tissues from the point of view of physiologically structured partial differential models, focusing on age synchronisation in the cell division cycle in cell populations and its control at phase transition checkpoints. We show how a recent fluorescence-based technique (FUCCI) performed at the single cell level in proliferating cell populations allows identifying model parameters and how it may be applied to investigate healthy and cancer cell populations. We show how this modelling approach allows designing original optimisation methods for cancer chronotherapeutics, by controlling eigenvalues of differential operators underlying proliferation dynamics, in tumour and in healthy cell populations.
    Proceedings of ICNAAM 2011, Kallithea Chalkidis (Greece); 01/2011
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    Mathematical Modelling of Natural Phenomena 01/2009; 4(3):12-67. · 0.56 Impact Factor
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    ABSTRACT: The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.
    Annual Review of Pharmacology 01/2010; 50:377-421. · 21.54 Impact Factor

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