Background: The goal of our work is to understand the mechanisms by which hyperthermia radiosensitizes cells. The molecular change(s) identified in these mechanisms would then be targeted for the development of pharmacological radiosensitizer

Methods: We are pursuing a two-fold approach toward the development of these compounds. Specifically, we are developing agents with improved ability to enhance the radiosensitizing effects of hyperthermia and delineating more completely the molecular targets involved in radiosensitization based on new knowledge of the pathways involved in DNA repair.

Results: It is becoming increasingly apparent that multiple molecular changes can contribute to the radiosensitization that is induced by heat, when the TER (thermal enhancement ratio) is above the 1.5-1.7 range. We have evidence suggesting that different mechanisms contribute to the TER at temperatures at and above 43^OC as compared to those induced at 41^OC. At moderate temperatures heat effects on the MRE11-RAD50-NBS1-complex (which is involved in both known pathways for DNA double-strand break repair) appear to contribute to radiation sensitivity. These effects correlated with TER 1:00 - 1.75. At temperatures above 43^OC, the masking of MAR DNA appears to contribute to radiation sensitivity. The masking effect correlates with TER above 1.7. Redistribution of the nucleolar protein, nucleophosmin, appears to be responsible for the masking of MAR DNA. Our current results suggest that thermal enhancing agents can cause mechanisms that normally require 43^OC to occur at 42 and possibly 41^OC.

Conclusions: The molecular events involved in heat-induced radiosensitization should make an ideal molecular target for the development of radiosensitizers.