Intracellular Accumulation and Mechanism of Action of Doxorubicin in a Spatio-temporal Tumor Model

Jackson, Trachette L.

doi:10.1006/jtbi.2003.3156

Cited by 68 publications

(58 citation statements)

References 27 publications

(24 reference statements)

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“…The remaining two (a discrete, compartment-based, model and a continuum, PDE-based, model) are tailored to the specific problem of drug delivery from a single vessel to a homogeneous tumour cord, assuming radial symmetry. All were built on a binding model involving extracellular drug and free and bound intracellular drug, which extends those of [12] and [17] by allowing drug binding to be saturable and reversible.…”

Section: Discussionmentioning

confidence: 99%

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Mathematical and computational models of drug transport in tumours

Groh

Hubbard

Jones

et al. 2014

J. R. Soc. Interface.

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The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a 'tumour cord' geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are 'pharmacokinetically resistant' to chemotherapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

“…A model for the tumour cord is then readily obtained as the system of partial differential equations (PDEs) [10,12] …”

Section: Radially Symmetric Continuum Modelmentioning

confidence: 99%

Mathematical and computational models of drug transport in tumours

Groh

Hubbard

Jones

et al. 2014

J. R. Soc. Interface.

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“…In accordance with the formulation in Jackson et al, 23,24 we assumed constant tumor structure and compositions throughout the vascularized tumor domains, implying that the tumor cell number density, the vasculature density, and the volume fraction of the tumor ECS in these tumor regions remain constant. To avoid explicitly modeling angiogenesis processes, we invoked the assumption that progressive tumor growth or shrinkage is accompanied by proportional numbers of blood vessels being created or destroyed, respectively.…”

Section: The Modelmentioning

confidence: 90%

Modeling Recombinant Immunotoxin Efficacies in Solid Tumors

Chen

Kim

et al. 2008

Ann Biomed Eng

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Effectiveness of cancer therapy is improved by the use of recombinant immunotoxins (RITs) that target membrane proteins unique to malignant tumor cells. Although RIT antitumor activity in vivo can always be improved with larger doses, clinical restriction on the dose toleration makes it critical to explore how RIT antitumor activity can be maximized without resorting to dose elevation. In this work, a mathematical model was developed to explore functional correlations between the properties of several recombinant immunotoxins and their antitumor efficacies in vivo. Simulations were compared with experimental data of human tumor xenografts grown on nude mice to assess parameters critical to optimal antitumor activity. We dissected out or held constant as many parameters of the model as possible to investigate the effect of the remaining parameters on the behavior of the system as a whole. Empirical correlations between immunotoxin binding affinity and the target binding site density were obtained for several recombinant immunotoxins targeting either human A431 carcinoma or CD46 Burkitt's lymphoma. Simulations reinforced the idea of binding site barrier for drug diffusion and suggested that optimal antitumor activity was achieved when the binding affinity is logarithmically dependent on the target binding site density.

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“…The authors compared the tumour response to an equal amount of drug administered either by bolus injection or by continuous infusion. Jackson based herself on this work to develop a model of the action of an anti-cancer agent (doxorubicin) on tumour growth [72]. This model is composed of a submodel of tumour growth coupled to a three-compartment submodel of intratumour drug concentration (extracellular space, intracellular fluid space, nucleus space) and to a submodel of the plasma concentration of the drug.…”

Section: Ode Models For Growing Cell Populations With Drug Controlmentioning

confidence: 99%