Modelling The In Vitro Kinetics Of The Anti-Cancer Agent Topotecan
Catherine
Lloyd
Auckland Bioengineering Institute, University of Auckland
Model Status
This model is valid CellML and has consistent units but is unable to be integrated in OpenCell or COR because it is unsuitably constrained.
Model Structure
The compartmental approach to modelling the kinetics of a drug can be used to provide a mathematical description of the characteristcis of that drug and how it is delivered to a particular target. With this aim in mind, Evans et al. propose a compartmental model for the anti-cancer agent topotecan (TPT). The mathematical equations used to describe the physiological processes are based on biological assumptions, and the model parameters are estimated using high performance liquid chromatograpy data.
TPT is a water soluble anti-cancer drug which has been approved for use against ovarian and small cell lung carcinomas. The drug's molecular target is DNA topoismerase I, an enzyme which resolves topological distortions in DAN by cleavage and re-ligation of one strand of the double stranded helix. TPT administration traps topoismerase I in a covalently bound intermediate complex with DNA. When the DNA replication machinary collides with this complex, the double stranded DNA breaks apart.
The activity of TPT is pH dependent. AT physiological pH the active form of the agent is not stable, and it undergoes reversible hydrolisis to form the more stable, inactive form. The reversible hydrolisis of TPT is first modelled by a linear, two compartment model. This simple model then forms the basis of a cell based model for drug activity in live cell experiments (see below).
The cell based model has been described here in CellML (the raw CellML description of the Evans et al. 2004 model can be downloaded in various formats as described in ).
The complete original paper reference is cited below:
A mathematical model for the in vitro kinetics of the anti-cancer agent topotecan, Neil D. Evans, Rachel J. Errington, Micchael Shelley, Graham P. Feeney, Michael J. Chapman, Keith R. Godfrey, Paul J. Smith, Michael J. Chappell, 2004, Mathematical Biosciences, 189, 185-217. PubMed ID: 15094319
cell diagram
Schematic diagram of the mathematical model used to investigate the effect of injecting the anticancer drug TPT into a culture of human lymphoma cells.
Lm
TPT-L concentration in the medium
Hm
TPT-H concentration in the medium
Lc
TPT-L concentration in the cytoplasm
Hc
TPT-H concentration in the cytoplasm
Ln
TPT-L concentration in the nucleus
Topotecan
cancer
Cancer
topotecan
pharmacokinetics
Drug Kinetics
Keith
Godfrey
R
keyword
2004-06
The University of Auckland, Bioengineering Institute
Catherine
Lloyd
May
Neil
Evans
D
15094319
Graham
Feeney
P
This is the CellML descripition of Evans et al.'s 2004 mathematical model for the in vitro kinetics of the anti-cancer agent topotecan.
Michael
Chapman
J
Michael
Chappell
J
The University of Auckland
The Bioengineering Institute
Michael
Shelly
Catherine Lloyd
Mathematical Biosciences
Rachel
Errington
J
A mathematical model for the in vitro kinetics of the anti-cancer agent topotecan
189
185
217
Paul
Smith
J
2004-05-29
c.lloyd@auckland.ac.nz
Evans et al.'s 2004 mathematical model for the in vitro kinetics of the anti-cancer agent topotecan.