Analysis of radiation effects using a combined cell cycle and multistage carcinogenesis model

Abstract

Purpose To study radiation effects using a combined cell cycle and multistage clonal expansion model that includes processes of damage, repair, apoptosis, and mutation. The model includes endogenous and radiation induced damage causing progression of cells from normal, to damaged, to initiated, to initiated damage, to malignant status. We utilize complementary deterministic and stochastic versions of the model that share the same transition rates. The deterministic version is used to calibrate model rates for cell cycle progression, damage, checkpoint delay, repair, and apoptosis, and to implement tissue homeostasis. The stochastic version is used to predict the cancer hazard and survival. Results We calibrated transition rates in the deterministic version of the model to fit flow cytometry-based clonogenic survival data for Chinese hamster V79 cells and for HeLa × skin fibroblast human hybrid cells exposed to sparsely ionizing radiation during different phases of the cell cycle. We also calibrated repair and malignant transformation rates to fit neoplastic transformation data for HeLa × skin fibroblast human hybrid cells. We found that induced repair in G2 phase explained the low-dose hypersensitivity for survival in both cell lines, and a different induced repair process explained the neoplastic transformation data. Conclusion The shape of the induced repair curves for G2-phase survival and neoplastic transformation differ significantly, suggesting that these low-dose phenomena differ in regulation and, in fact, may be mechanistically unrelated.