A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport

IEEE/ACM Trans Comput Biol Bioinform. 2012 Nov-Dec;9(6):1595-606. doi: 10.1109/TCBB.2012.118.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Biological Transport
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / physiology
  • Cell Hypoxia / physiology
  • Cell Survival / drug effects
  • Computer Simulation
  • Humans
  • Models, Biological*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Neural Networks, Computer
  • Tirapazamine
  • Triazines / pharmacokinetics
  • Triazines / pharmacology
  • Tumor Microenvironment / drug effects

Substances

  • Antineoplastic Agents
  • Triazines
  • Tirapazamine