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      Predicting drug pharmacokinetics and effect in vascularized tumors using computer simulation

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          Abstract

          In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC 50 concentration). For doxorubicin the effect of hypoxia and hypoglycemia (“nutrient effect”) is isolated and shown to further increase cell inhibition heterogeneity and double the IC 50, both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment.

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          Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice.

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            Pathology: cancer cells compress intratumour vessels.

            The delivery of therapeutic drugs to solid tumours may be impaired by structural and functional abnormalities in blood and lymphatic vessels. Here we provide evidence that proliferating cancer cells cause intratumour vessels to compress and collapse. By reducing this compressive mechanical force and opening vessels, cytotoxic cancer treatments have the potential to increase blood perfusion, thereby improving drug delivery.
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              Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies.

              Tissue hypoxia occurs where there is an imbalance between oxygen supply and consumption. Hypoxia occurs in solid tumours as a result of an inadequate supply of oxygen, due to exponential cellular proliferation and an inefficient vascular supply. It is an adverse prognostic indicator in cancer as it is associated with tumour progression and resistance to therapy. The expression of several genes controlling tumour cell survival are regulated by hypoxia, e.g., growth factors governing the formation of new blood vessels, and hypoxia-responsive transcription factors modulating the expression of genes, which promote tumour cell survival. This review outlines some of the pathways by which tumour hypoxia leads to chemotherapeutic resistance, directly due to lack of oxygen availability, and indirectly due to alterations in the proteome/genome, angiogenesis and pH changes. Some innovative therapies are also detailed which may potentially minimise or eliminate these problems associated with targeting solid tumours.
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                Author and article information

                Contributors
                Vittorio.Cristini@uth.tmc.edu
                Journal
                J Math Biol
                Journal of Mathematical Biology
                Springer-Verlag (Berlin/Heidelberg )
                0303-6812
                1432-1416
                10 September 2008
                April 2009
                : 58
                : 4-5
                : 485-510
                Affiliations
                [1 ]Department of Mathematics, University of California, Irvine, CA USA
                [2 ]Department of Biomedical Engineering, University of Texas, Austin, TX USA
                [3 ]Department of Biomedical Engineering, University of California, Irvine, CA USA
                [4 ]School of Health Information Sciences, University of Texas Health Science Center, 7000 Fannin, Suite 850A, Houston, TX 77030 USA
                [5 ]Center for Nanomedicine, Brown Foundation Institute of Molecular Medicine, Department of Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, TX USA
                [6 ]Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX USA
                [7 ]Department of Bioengineering, Rice University, Houston, TX USA
                [8 ]Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX USA
                Article
                214
                10.1007/s00285-008-0214-y
                2782117
                18781304
                f8f40ad2-f8bb-4b1c-9f91-bd9d39316591
                © The Author(s) 2008
                History
                : 23 February 2007
                : 30 January 2008
                Categories
                Article
                Custom metadata
                © Springer-Verlag 2009

                Quantitative & Systems biology
                therapy,92c45,in silico,pharmacokinetics,simulation,prediction
                Quantitative & Systems biology
                therapy, 92c45, in silico, pharmacokinetics, simulation, prediction

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