Modification of thermosensitivity and chemosensitivity induced by combined treatments with hyperthermia and adriamycin

Both adriamycin (ADM) and hyperthermia show thermal chemo-enhancement. Tolerance induction against ADM in heated cells has been reported resulting in clinical difficulty of cancer therapy. We investigated thermo-enhancement induced with ADM (0.2 μg/ml) treatment alone or combined with ADM and 42°C hyperthermia in Chinese hamster V79 cells in vitro. Intracellular accumulation of hsc70 and hsp72 proteins after hyperthermia or ADM was observed to examine the possible relationship between cell killing effect and their accumulations. Thermosensitivity of V79 cells at 42°C after the simultaneous treatments with ADM showed marked thermo-enhancement within the short-term treatments for less than 1 h, while the combined treatments for longer than 1 h, the cells showed reduced thermosensitivity. Survival from the simultaneous treatments for less than 1 h was reduced markedly less than the single treatment both with ADM or 42°C hyperthermia alone. Thermotolerance was markedly induced in a step-up hyperthermia (42°C 2 h - 44°C). The combined treatments with ADM and 44°C hyperthermia following the 42°C preheating alone does not inhibit thermotolerance development. The combined treatments with ADM and 42°C preheating showed markedly interactive cell killing, but no thermo-enhancement to the following 44°C hyperthermia was shown. The leveling slope of the 44°C heating period - survival curve was drawn. In the Western blot analyses, hsc70 existed constitutively in the V79 cells. Following the 42 or 44°C hyperthermia alone, intracellular accumulation of hsp72 was determined. ADM treatment alone did not induce any accumulation of hsp72. In the simultaneous treatments with ADM and hyperthermia, the accumulation of hsp72 was markedly reduced. The accumulation of hsp72 after the combined treatment with ADM and hyperthermia was not observed as markedly as that after hyperthermia alone.