Elimination of dose-rate effects by mild hyperthermia.

OBJECTIVE

Preferential amplification of low dose-rate irradiation toxicity in tumor cells is one way of improving presently applied brachytherapy. Low temperature hyperthermia applied to a tumor volume during irradiation is one candidate for reaching this goal. The ranges of relevant temperatures and dose-rate have been determined in a tissue culture system. In addition, the role of inhibition of sublethal damage repair in inhibition of dose-rate sparing has been investigated.

METHODS

Dose-rate modification by long duration, mild hyperthermia was investigated in rat 9L gliosarcoma cells at dose-rates between 0.0833 and 132 Gy/hr. Enhancement of toxicity was measured using the colony formation technique.

RESULTS

A biphasic dose-rate effect curve was observed when cells were irradiated at 37 degrees C. The dose required to kill 99% of cells irradiated at 37 degrees C increased sharply between 20 and 5 Gy/hr and also below 1 Gy/hr. When cells were irradiated at 41 degrees C, dose-rate sparing disappeared from 132 to 0.0833 Gy/hr. Elimination of dose-rate sparing appeared to be caused by both inhibition of sublethal damage repair and blockage of cell proliferation. The temperature threshold for sensitizing low dose-rate irradiation was determined at temperatures between 24 degrees C and 41 degrees C during 0.5 Gy/hr irradiation. Temperature dependent sensitization occurred above 39 degrees C. The mechanisms by which low temperature hyperthermia sensitizes low dose-rate irradiation was investigated using split dose experiments. Survival curve shoulder recovery was inhibited when cells were incubated at 41 degrees C between acute irradiations. This effect appeared to be caused by both inhibition of recovery from sublethal damage from the first radiation and preheating sensitization of the second irradiation. In single acute dose experiments, sensitization from preheating at 41 degrees C increased gradually over a 6 hr period.

CONCLUSIONS

The mechanism by which 41 degrees C hyperthermia sensitizes low dose-rate irradiation is inhibition of radiation repair at medium dose rates and inhibition of repair and proliferation at very low dose rates. If low temperature hyperthermia is able to sensitize human tumor cells to brachytherapy similar to what has been described with 9L gliosarcoma cells, the addition of this modality could potentially greatly improve presently applied therapy.