Abstract

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.

摘要

简介：超过30年前，根据经验推导了43°C的累积等效分钟（CEM43）热剂量模型，尽管监管网络模型已经问世，它仍可作为热疗方案的基准。但是，CEM43在无法预测复杂的时变曲线（热阻，降压加热）的效果，无法预测与药物治疗的协同效果或无法解释细胞系在耐热性方面的特异性方面受到一些限制。

目标：基于监管网络模型定义一种新的热损伤通用预测工具。确定引起热阻的生物学参数。

材料：从文献中收集的热疗后细胞存活的比较研究（11种出版物中的17套，涵盖了8种不同组织的14种不同细胞系）。

结果：动力学模型根据暴露的幅度和持续时间以及分子伴侣表达水平准确描述细胞存活。在正方形热疗的情况下，细胞存活的近似分析表达是从动力学模型得出的，并与CEM43描述进行了比较。分子伴侣蛋白的表达水平定义了给定细胞系的耐热性，并且可以通过易于使用的图形工具根据单个实验结果进行估算。

结论：此处提供的工具可用于设计结合分子伴侣的热疗和化学疗法的治疗方法，也可用于通过分子伴侣的事先生化筛选来设计个性化的高温治疗。这些工具可以有利地代替CEM43的描述。