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Lookup NU author(s): Professor Andrew FilbyORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2021 James, Filby, Brown, Summers, Francis and Rees.Many chemotherapeutic drugs target cell processes in specific cell cycle phases. Determining the specific phases targeted is key to understanding drug mechanism of action and efficacy against specific cancer types. Flow cytometry experiments, combined with cell cycle phase and division round specific staining, can be used to quantify the current cell cycle phase and number of mitotic events of each cell within a population. However, quantification of cell interphase times and the efficacy of cytotoxic drugs targeting specific cell cycle phases cannot be determined directly. We present a data driven computational cell population model for interpreting experimental results, where in-silico populations are initialized to match observable results from experimental populations. A two-stage approach is used to determine the efficacy of cytotoxic drugs in blocking cell-cycle phase transitions. In the first stage, our model is fitted to experimental multi-parameter flow cytometry results from untreated cell populations to identify parameters defining probability density functions for phase transitions. In the second stage, we introduce a blocking routine to the model which blocks a percentage of attempted transitions between cell-cycle phases due to therapeutic treatment. The resulting model closely matches the percentage of cells from experiment in each cell-cycle phase and division round. From untreated cell populations, interphase and intermitotic times can be inferred. We then identify the specific cell-cycle phases that cytotoxic compounds target and quantify the percentages of cell transitions that are blocked compared with the untreated population, which will lead to improved understanding of drug efficacy and mechanism of action.
Author(s): James DW, Filby A, Brown MR, Summers HD, Francis LW, Rees P
Publication type: Article
Publication status: Published
Journal: Frontiers in Bioinformatics
Year: 2021
Volume: 1
Online publication date: 27/04/2021
Acceptance date: 01/04/2021
Date deposited: 23/11/2023
ISSN (electronic): 2673-7647
Publisher: Frontiers Media SA
URL: https://doi.org/10.3389/fbinf.2021.662210
DOI: 10.3389/fbinf.2021.662210
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