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The effect of hyperthermia and bupivacaine, alone and in combination, on the clonogenic activity of a human melanoma cell line was investigated. The time-temperature relationship of exponentially growing cells was defined in the range of 41-45 degrees C. All the survival curves were exponential and the Arrhenius plot was linear over the temperature range tested. The survival curve of bupivacaine-treated cells was also exponential after an initial shoulder. Bupivacaine affected cell survival mainly through an ATP depletion because of deep alterations of mitochondria, essentially due to changes in the physical state of membrane lipids. The analysis of the interaction between hyperthermia and bupivacaine, performed with an isobolar method, demonstrated a synergism of response at all combinations tested, but only with simultaneous exposure. Such a response did not depend on an impairment of the energy-yielding processes, but may be ascribed to combined effects of both agents on cell structure and function. The hyperthermic enhancement achieved by low bupivacaine concentrations allowed to achieve a preestablished cell killing with a reduced exposure time (e.g., 50 min) and with a temperature (42 degrees C) generally accepted as clinically achievable. Therefore, a combined modality in which local treatment with bupivacaine was coupled to local heating could result in high local damage with reduced systemic complications.