Thermotolerance and radiation sensitizing effects of long duration, mild temperature hyperthermia

Clinical application of long duration hyperthermia at temperatures < 42 degrees C has traditionally been avoided because of the possibility of chronic thermotolerance development, such as is observed with rodent cells. In support of long duration hyperthermia, both rodent and human cells have been shown to be sensitized to low dose-rate irradiation by simultaneous heating at 40 or 41 degrees C. The relationship between these supposed contradictory responses to hyperthermia were investigated in rat 9L gliosarcoma cells in vitro. Thermotolerance developed during 41 degrees C heating with or without concurrent low dose-rate irradiation. Thermotolerance reached a maximum within 6 h during 41 degrees C heating and remained stable for at least 24 h. When cells were returned to 37 degrees C after heating at 41 degrees C for 6 h, thermotolerance remained stable for at least 12 h. The time course of thermotolerance development correlated with that of induction of 41 degrees C radiation sensitization. Radiation sensitization, on the other hand, was shown to be independent of thermotolerance because the protein synthesis inhibitor cycloheximide prevented thermotolerance induction but had no effect on radiation sensitization. We conclude that thermotolerance development during concurrent clinical application of long duration mild temperature hyperthermia and low dose-rate irradiation should not be a factor in altering treatment outcome.