Computational modeling of the effect of the mismatch repair protein hMLH1 upon cell cycle responses and cytotoxicity of 5-iododeoxyuridine (IUdR) in colon cancer cells. Free

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Previous studies in our laboratory have described increased and preferential radiosensitization of mismatch repair (MMR) deficient colon cancer cells with 5-iododeoxyuridine (IUdR). We have shown that mismatch repair deficient colon cancer cells incorporate 25% to 42% more IUdR than mismatch repair competent cells, and that IUdR and IR interact to produce up to three-fold greater radiosensitivity in MMR deficient cells. The present study utilizes mathematical models to describe the effects of IUdR incorporation upon the cell cycle for the purpose of increasing IUdR radiosensitivity in mismatch repair deficient cells by improving the timing of the ionizing radiation (IR) to maximize the DNA damage caused by IR-induced base excision repair responses. To date, two computational models have been developed towards this goal, the first being a stochastic model of the progression of cell cycle states, which gives the cell cycle distribution at any given time for two synchronized colon cancer cell lines, one proficient for mismatch repair and the other deficient, treated with and without IUdR. The second model defines the relation between the percentage of cells in the different cell cycle states at any time, and the corresponding IUdR incorporation at this point. Together, these models can be combined to predict IUdR incorporation at any time in the cell cycle by substituting the distributions of the first model into the second model. Ultimately these mathematical models can be used to maximize therapeutic gain in mismatch repair deficient cells by predicting the optimal dose and the optimal time in the cell cycle for delivery of IUdR and IR to increase the synergistic action of the DNA repair responses to IUdR- and IR- induced damage. Further computational modeling studies are being developed to this purpose.