Assessing chemotherapy dosing strategies in a spatial cell culture model

Abstract

Predicting patient responses to chemotherapy regimens is a major challenge in cancer treatment. Experimental model systems coupled with quantitative mathematical models to calculate optimal dose and frequency of drugs can enable improved chemotherapy regimens. Here we developed a simple approach to track two-dimensional cell colonies composed of chemo-sensitive and resistant cell populations via fluorescence microscopy and coupled this to computational model predictions. Specifically, we first developed multiple 4T1 breast cancer cell lines resistant to varying concentrations of doxorubicin, and demonstrated how heterogeneous populations expand in a two-dimensional colony. We subjected cell populations to varied dose and frequency of chemotherapy and measured colony growth. We then built a mathematical model to describe the dynamics of both chemosensitive and chemoresistant populations, where we determined which number of doses can produce the smallest tumor size based on parameters in the system. Finally, using an in vitro model we demonstrated multiple doses can decrease overall colony growth as compared to a single dose at the same total dose. In the future, this system can be adapted to optimize dosing strategies in the setting of heterogeneous cell types or patient derived cells with varied chemoresistance.