Radiation-induced cell cycle perturbations: a computational tool validated with flow-cytometry data

Abstract

Cell cycle progression can be studied with computational models that allow to describe and predict its perturbation by agents as ionizing radiation or drugs. Such models can then be integrated in tools for pre-clinical/clinical use, e.g. to optimize kinetically-based administration protocols of radiation therapy and chemotherapy. We present a deterministic compartmental model, specifically reproducing how cells that survive radiation exposure are distributed in the cell cycle as a function of dose and time after exposure. Model compartments represent the four cell-cycle phases, as a function of DNA content and time. A system of differential equations, whose parameters represent transition rates, division rate and DNA synthesis rate, describes the temporal evolution. Initial model inputs are data from unexposed cells in exponential growth. Perturbation is implemented as an alteration of model parameters that allows to best reproduce cell-cycle profiles post-irradiation. The model is validated with dedicated in vitro measurements on human lung fibroblasts (IMR90). Cells were irradiated with 2 and 5 Gy with a Varian 6 MV Clinac at IRCCS Maugeri. Flow cytometry analysis was performed at the RadBioPhys Laboratory (University of Pavia), obtaining cell percentages in each of the four phases in all studied conditions up to 72 h post-irradiation. Cells show early $${\text{G}}_{2}$$ G 2 -phase block (increasing in duration as dose increases) and later $${\text{G}}_{1}$$ G 1 -phase accumulation. For each condition, we identified the best sets of model parameters that lead to a good agreement between model and experimental data, varying transition rates from $${\text{G}}_{1}$$ G 1 - to S- and from $${\text{G}}_{2}$$ G 2 - to M-phase. This work offers a proof-of-concept validation of the new computational tool, opening to its future development and, in perspective, to its integration in a wider framework for clinical use.

The Influence of Different γ-Irradiation Patterns on Factors that May Affect Cell Cycle Progression in Male Rats

“…On the contrary, if the DNA is unsuccessfully repaired, the cell may die and exit from the cycle or continue with genome instability. 42 When compared to the control group, ionizing irradiation increases G2/M, especially at the dose of 2 GyX4, increases S phase at all doses and patterns of radiation, decreases G0/G1, especially at the dose of 2 GyX4, and decreases subG1 at all doses. TGF-β induced a delay in G2/M progression.…”

Analysis of nuclear maturation, DNA damage and repair gene expression of bovine oocyte and cumulus cells submitted to ionizing radiation

“…BAX is a member of the Bcl-2 family of proteins and functions as a pro-apoptotic death effector ( Chong et al, 2000 ). Because the cell cycle is affected by irradiation, and radiosensitivity depends on cell cycle position and cell cycle progression, it is not surprising that some association between apoptosis and radiosensitivity has been observed ( Lonati et al, 2021 ; Pawlik and Keyomarsi, 2004 ). However, our analysis showed a decrease of pro-apoptotic gene BAX mRNA expression with increasing radiation dose, indicating an absence of apoptotic response.…”

An Integrated Analysis of the Response of Colorectal Adenocarcinoma Caco-2 Cells to X-Ray Exposure

“…In this research framework, this work sets the basis for future in vitro experimental studies [as well as for the development of computational models ( 30 )] to develop new therapeutic strategies or explore synergistic effects in combined treatments ( e.g. radiation, including the effect of fractionation as in a more realistic clinical setting, and other cytotoxic agents as chemotherapeutic drugs) using Caco-2 cell line [also, foreseeing the possibility of a 3D culture to better mimic the in vivo situation ( 31 )] as a model for colorectal cancer.…”