Mammalian cell sensitivity to hyperthermia in various cell lines: a new universal and predictive description.

Introduction: The Cumulative Equivalent Minute at 43 °C (CEM43) thermal dose model has been empirically derived more than 30 years ago and still serves as a benchmark for hyperthermia protocols despite the advent of regulatory network models. However, CEM43 suffers from several limitations regarding its inability to predict the effect of complex time varying profiles (thermotolerance, step-down heating), to predict synergistic effects with drug treatments or to explain the specificity of a cell line in thermal resistance.Objective: Define a new generic predictive tool for thermal injury based on regulatory network models. Identify the biological parameters that account for the thermal resistance.Materials: Comparative study of cell survival upon hyperthermia collected from literature (17 sets in 11 publications that cover 14 different cell lines from 8 different tissues).Results: A dynamical model describes accurately cell survival according to the amplitude and duration of exposure but also molecular chaperone expression level. In the case of square shape hyperthermia, approximated analytical expression of the cell survival is derived from the dynamical model and compared to CEM43 description. The molecular chaperone expression level defines the thermal resistance of a given cell line and can be estimated from a single experimental result through an easy-to-use graphical tool.Conclusion: The tools offered here can be useful for designing treatments combining hyperthermia and chemotherapy targeting molecular chaperones, but also for designing personalized hyperthermic treatment by prior biochemical screening of molecular chaperones. These tools could advantageously replace the description of CEM43.

Dynamical thermal dose models and dose time-profile effects.

Introduction: Models of dose-effect relationships seek systematic and predictive descriptions of how cell survival depends on the level and duration of the stressor. The CEM43 thermal dose model has been empirically derived more than thirty years ago and still serves as a benchmark for hyperthermia protocols despitethe advent of regulatory network models. Objective: In this paper, we propose and realize a simple experimental test to assess whether mechanistic models can prove more reliable indicators for some protocols. We define two time-asymmetric hyperthermia profiles, faster rise than decay or slower rise than decay, for which the CEM43 model predicts the same survival while a regulatory network model predicts significant differences. Materials: Experimental data (both control 37°C and hyperthermia assays) were collected from duplicate HeLa cell cultures. Cells were imaged before and 24, 48 and 72 h after the hyperthermia assay double-stained with fluorescein-5-isothiocyanate (FITC)-labeled annexin V and propidium iodide for detecting cell death. Results: Survival experiments of HeLa cells show that a fast temperature rise followed by a slow decay can be twice more lethal than the opposite, consistently with the prediction of the network model. Conclusions: Using a model reduction approach, we obtained a simple nonlinear dynamic equation that identifies the limited repair capacity as the main factor underlying the dose-asymmetry effect and that could be useful for refining thermal doses for dynamic protocols.