Reactions of normal and tumor cells and tissues to hyperthermia in combination with ionizing radiation. Review

The review presents an analysis of literature data on the modifying effect of hyperthermia (HT) on the radiation response of normal and tumor cells and tissues, as well as on the use of HT to increase the radiosensitivity of tumors. The analyzed data indicate that the radiosensitizing effects of HT are manifested in the additive or synergistic enhancement of cytotoxicity in irradiated bio-objects. The degree of such enhancement depends on the level of heating, radiation dose, the sequence of the exposures and the interval between them, types of tissue, etc. The radiosensitizing effects of HT are manifested not only on tumors, but also on normal cells and tissues too. This circumstance requires determination of the therapeutic gain factor in different cases of application of the thermotherapy of tumors. Heat-shock proteins (HSPs), which are one of the factors of tumor resistance to thermo-, chemo- and radiotherapy, are actively involved in cellular reactions to HT and radiation exposure. It is shown that the functioning of HSP90 is necessary for the post-radiation repair of nuclear DNA breaks. In addition, HSP90, HSP70 and HSP27 are powerful suppressors of apoptosis and help the stressed cell to reactivate or degrade stress-denatured proteins. In the case of a combination of HT and radiation, these HSPs form complexes with denatured intracellular proteins and can no longer act as radioprotectors and blockers of apoptosis. Thus, recruitment of HSPs to protect against the proteotoxic effects of HT occurs to the detriment of HSP-mediated radioresistance of cancer cells and, consequently, contributes to their radiosensitization. However, the induction and transient increase in the levels of HSP90, HSP70 and HSP27 in cells that have survived HT can make them for some period thermotolerant and more radioresistant that should be taken into consideration in the case of consequtive combining HT and radiation therapy.