A mathematical model for cisplatin cellular pharmacodynamics.
A simple theoretical model for the cellular pharmacodynamics of cisplatin is presented. The model, which takes into account the kinetics of cisplatin uptake by cells and the intracellular binding of the drug, can be used to predict the dependence of survival (relative to controls) on the time course of extracellular exposure. Cellular pharmacokinetic parameters are derived from uptake data for human ovarian and head and neck cancer cell lines. Survival relative to controls is assumed to depend on the peak concentration of DNA-bound intracellular platinum. Model predictions agree well with published data on cisplatin cytotoxicity for three different cancer cell lines, over a wide range of exposure times. In comparison with previously published mathematical models for anticancer drug pharmacodynamics, the present model provides a better fit to experimental data sets including long exposure times (approximately 100 hours). The model provides a possible explanation for the fact that cell kill correlates well with area under the extracellular concentration-time curve in some data sets, but not in others. The model may be useful for optimizing delivery schedules and for the dosing of cisplatin for cancer therapy.
El-Kareh
Ardith W
AW
ARL-Microcirculation Division, University of Arizona, Tucson, AZ 85724-5051, USA. elkareh@u.arizona.edu
Secomb
Timothy W
TW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D015233:Models, Statistical; D008962:Models, Theoretical; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013997:Time Factors
D000970:Antineoplastic Agents; D002945:Cisplatin