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A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport
Nabila Kazmi1, M A Hossain, Roger M Phillips
1School of Computing, Engineering and Information Sciences, Northumbria University, Room PB 043, Pandon Building, Newcastle upon Tyne, Tyne and Wear NE1 8ST, United Kingdom. sonahrazia@yahoo.com
Abstract:
Bioreductive drugs are a class of hypoxia selective drugs that are designed to eradicate the hypoxic fraction of solid tumors. Their activity depends upon a number of biological and pharmacological factors and we used a mathematical modeling approach to explore the dynamics of tumor growth, infusion, and penetration of the bioreductive drug Tirapazamine (TPZ). An in-silico model is implemented to calculate the tumor mass considering oxygen and glucose as key microenvironmental parameters. The next stage of the model integrated extra cellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints. The tumor microenvironments strongly influenced tumor morphology and growth rates. Once the growth model was established, a hybrid model was developed to study drug dynamics inside the hypoxic regions of tumors. The model used 10, 50 and 100 \mu {\rm M} as TPZ initial concentrations and determined TPZ pharmacokinetic (PK) (transport) and pharmacodynamics (cytotoxicity) properties inside hypoxic regions of solid tumor. The model results showed that diminished drug transport is a reason for TPZ failure and recommend the optimization of the drug transport properties in the emerging TPZ generations. The modeling approach used in this study is novel and can be a step to explore the behavioral dynamics of TPZ.
Insights
Mathematical modeling revealed that poor drug transport limits the effectiveness of Tirapazamine (TPZ) in solid tumors. Optimizing TPZ transport properties is crucial for future generations of this hypoxia-selective cancer drug.
Area of Science:
- Computational biology
- Cancer pharmacology
- Tumor microenvironment dynamics
Background:
- Bioreductive drugs target the hypoxic fraction of solid tumors.
- Tirapazamine (TPZ) is a hypoxia-selective drug with potential anti-cancer activity.
- Tumor microenvironment significantly impacts drug efficacy.
Purpose of the Study:
- To explore the dynamics of tumor growth, drug infusion, and penetration using mathematical modeling.
- To investigate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of TPZ in hypoxic tumor regions.
- To identify factors limiting TPZ efficacy and suggest optimization strategies.
Main Methods:
- Developed an in-silico model to simulate tumor mass, considering oxygen and glucose levels.
- Integrated extracellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints.
- Utilized a hybrid model to study TPZ dynamics at initial concentrations of 10, 50, and 100 μM.
Main Results:
- Tumor microenvironments were found to strongly influence tumor morphology and growth rates.
- Diminished drug transport was identified as a key reason for TPZ failure in hypoxic tumor regions.
- The model successfully determined TPZ PK and PD properties within the tumor.
Conclusions:
- Mathematical modeling provides a novel approach to explore bioreductive drug dynamics.
- Optimization of drug transport properties is recommended for future TPZ generations.
- Understanding drug transport is essential for enhancing the efficacy of hypoxia-selective cancer therapies.
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