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Abstract
We investigated the possible mechanisms of hyperthermic enhancement of actinomycin D (AMD) cytotoxicity in a neoplastic cell line. The hyperthermic enhancement of AMD cytotoxicity depended on both the temperature and the sequence of the administration. The percentage survival of sumultaneous treatment of either 42 or 43°C hyperthermia with 5 μg/ml AMD was 42% or 2-2%, respectively, and the amount of AMD in the DNA (DNA-bound AMD) of simultaneous hyperthermia at either 42 or 43°C was 16.5 or 27.2 ng/106 cells, respectively. The percentage survival of sequential treatment of 5 μg/ml AMD following either 42 or 43°C hyperthennia was 55 or 46%, respectively. The amount of DNA-bound AMD of sequential hyperthermia at either 42 or 43°C was 10.8 or 21 7 ng/106 cells, respectively. In addition, the percentage survivals of the S-phase and G1--phase cells concomitantly treated with 43°C hyperthennia and 5 μg/ml of AMD were 1 4 and 92%, respectively, and the amounts of DNA-bound AMD of these S-phase and G1--phase cells were 28.2 and 1.6 ng/106 cells. These findings suggested that an increased amount of AMD in DNA was responsible for the hyperthermic enhancement of AMD cytotoxicity. When the GI-phase cells were treated with 5 μg/ml AMD alone, without hyperthermia, the amount of AMD in acid-soluble fraction of the G1--phase cells was quite low (0.3 ng/106 cells). However, concomitant hyperthermia treatment with AMD at the G1--phase significantly increased the AMD amount (1 6 ng/106 cells at 42°C, and 3.1 ng/106 cells at 43°C) up to a level equal to that in asynchronous (1-7 ng/106 cells) and S-phase cells (2.1 ng/106 cells) simultaneously treated with hyperthermia and AMD. It was suggested that hyperthermia altered the membrane permeability of the G1--phase cells. The increase of the AMD amount in the DNA might thus be the result of higher intracellular drug concentration.