Abstract 4265: Computational models of the role of base excision repair in sensitization of cancer cells to 5-fluorodeoxyuridine

Abstract

Abstract The purpose of this study is to computationally analyze the effect of inhibition of base excision repair (BER) in the response of cancer cells to treatment with 5-fluorodeoxyuridine. 5-fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine (5-FdU) are standard treatments for different solid tumors and especially for colon cancer. In the literature, it is shown that the depletion of uracil DNA glycosylase (UDG), one of the enzymes that initiate the BER pathway, enhanced the cytotoxicity of 5-FdU, making UDG a potential target to enhance efficacy of chemotherapeutic agents. It is also shown that the activity of UDG is significantly higher in colon cancer cells compared to normal tissue. We have developed a computational model of the BER pathway to capture the BER dynamics in colon cancer cell lines after treatment with 5-FdU. Our model is composed of a series of ordinary differential equations where the parameters are the kinetic rate constants and the enzyme concentrations. We have used the data from the literature to initially parameterize our models. We have then used least square estimation to find the parameters that will capture the BER time course for colon cancer cells after 5-FU treatment using the experimental data from the literature. We have performed sensitivity and identifiability analyses to determine the parameters that are reliably estimated. The experimental data from the literature showed that the depletion of UDG resulted in incorporation of uracil and 5-FU in the DNA. We have computationally replicated this effect by decreasing the protein concentration of UDG in the models and simulating the amount of remaining 5-FU in the DNA after BER with reduced activity has taken place. We have studied the depletion effect for different protein concentrations of UDG and the results have shown that the accumulation of 5-FU in these colon cancer cells correlate with the level of UDG. The suppression of UDG activity has the potential to enhance the outcome of treatment with 5FdU, and we will use the developed computational models to quantitatively optimize these effects in our future work. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. Computational models of the role of base excision repair in sensitization of cancer cells to 5-fluorodeoxyuridine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4265.