Intracellular accumulation and mechanism of action of doxorubicin in a spatio-temporal tumor model

A spatio-temporal model of tumor response to sequestered, intracellular doxorubicin is presented and simulated. An important feature of the model is the characterization of different mechanisms by which doxorubicin initiates the cell death cascade. The model predicts that the long-term response of the tumor to repeated rounds of therapy is very sensitive to changes in the threshold level of doxorubicin required to initiate apoptosis at the maximum rate. In fact, perturbations of this parameter mediate the difference between effective tumor regression and minimal growth delays. The model is also used to investigate which parameters are most influential in rendering the tumor drug resistant. Sensitivity analysis shows that decreasing cellular permeability, as opposed to decreasing sequestration rate or increasing cellular efflux, is the most effective way for tumor cells to overcome the growth control afforded by successive rounds of treatment. (C) 2003 Elsevier Science Ltd. All rights reserved.