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Probabilistic Modeling of DNA Mismatch Repair Effects on Cell Cycle Dynamics and Iododeoxyuridine-DNA Incorporation

Departments of ¹ Electrical Engineering and Computer Science and ² Radiation Oncology and the Case Integrative Cancer Biology Program, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, Ohio

Requests for reprints: Timothy J. Kinsella, Department of Radiation Oncology, LTR6068, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106-6068. Phone: 216-844-2530; Fax: 216-844-4799; E-mail: timothy.kinsella{at}UHhospitals.org.

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. [Cancer Res 2007;67(22):10993–11000]