Probabilistic modeling of DNA mismatch repair effects on cell cycle dynamics and iododeoxyuridine-DNA incorporation.

Abstract

Previous studies in our laboratory have described increased and preferential radiosensitization of mismatch repair-deficient (MMR(-)) HCT116 colon cancer cells with 5-iododeoxyuridine (IUdR). Indeed, our studies showed that MMR is involved in the repair (removal) of IUdR-DNA, principally the G:IU mispair. Consequently, we have shown that MMR(-) cells incorporate 25% to 42% more IUdR than MMR(+) cells, and that IUdR and ionizing radiation (IR) interact to produce up to 3-fold greater cytotoxicity in MMR(-) cells. The present study uses the integration of probabilistic mathematical models and experimental data on MMR(-) versus MMR(+) cells to describe the effects of IUdR incorporation upon the cell cycle for the purpose of increasing IUdR-mediated radiosensitivity in MMR(-) cells. Two computational models have been developed. The first is a stochastic model of the progression of cell cycle states, which is applied to experimental data for two synchronized isogenic MMR(+) and MMR(-) colon cancer cell lines treated with and without IUdR. The second model defines the relation between the percentage of cells in the different cell cycle states and the corresponding IUdR-DNA incorporation at a particular time point. These models can be combined to predict IUdR-DNA incorporation at any time in the cell cycle. These mathematical models will be modified and used to maximize therapeutic gain in MMR(-) tumors versus MMR(+) normal tissues by predicting the optimal dose of IUdR and optimal timing for IR treatment to increase the synergistic action using xenograft models and, later, in clinical trials.