Hyperthermic radiosensitization: mode of action and clinical relevance

Purpose: To provide an update on the recent knowledge about the molecular m echanisms of thermal radiosensitization and its possible relevance to therm oradiotherapy. Summary: Hyperthermia is probably the most potent cellular radiosensitizer known to date. Heat interacts with radiation and potentiates the cellular a ction of radiation by interfering with the cells' capability to deal with r adiation-induced DNA damage. For ionizing irradiation, heat inhibits the re pair of all types of DNA damage. Genetic and biochemical data suggest that the main pathways for DNA double-strand break (DSB) rejoining, non-homologo us end-joining and homologous recombination, are not the likely primary tar gets for heat-induced radiosensitization. Rather, heat is suggested to affe ct primarily the religation step of base excision repair. Subsequently addi tional DSB arise during the DNA, repair process in irradiated and heated ce lls and these additional DSB are all repaired with slow kinetics, the repai r of which is highly error prone. Both mis- and non-rejoined DSB lead to an elevated number of lethal chromosome aberrations, finally causing addition al cell killing. Heal-induced inhibition of DNA repair is considered riot t o result from altered signalling or enzyme inactivation but rather from alt erations in higher-order chromatin structure. Although, the detailed mechan isms are not yet known, a substantial body of indirect and correlative data suggests that heat-induced protein aggregation at the level of attachment of looped DNA to the nuclear matrix impairs the accessibility of the damage d DNA for the repair machinery or impairs the processivity of the repair ma chinery itself. Conclusion: Since recent phase III clinical trials have shown significant b enefit of adding hyperthermia to radiotherapy regimens for a number of mali gnancies, it will become more important again to determine the molecular ef fects underlying this success. Such information could eventually also impro ve treatment quality in terms of patient selection, improved sequencing of the heat and radiation treatments, the number of heat treatments, and multi modality treatments (i.e. thermochemoradiotherapy).