THERMAL-BEHAVIOR OF A HUMAN GLIOMA CELL-LINE AND ITS RESPONSE TO COMBINATIONS OF HYPERTHERMIA AND LONIDAMINE

The effect of hyperthermia and lonidamine, alone and in combination, o n the clonogenic activity of a human glioma cell line was investigated . The time-temperature relationship of asynchronous, exponentially gro wing cells was defined in the range of 40-45-degrees-C. All survival c urves were exponential and an Arrhenius plot for heat killing was line ar over the temperature range tested, with an activation energy of 192 Kcal/mol. The survival curve of lonidamine-treated cells was also exp onential after an initial shoulder. The analysis of the interaction be tween lonidamine and hyperthermia, performed by the isobolar method, d emonstrated an additivity of response so that the effectiveness of the combined treatment was the result of two independent effects. Lonidam ine inhibits the neoplastic growth mainly through an ATP depletion, bu t the thermal killing was not mediated by the drug-induced changes in the energy status of the cell. The effectiveness of the combined treat ment was strongly influenced by the schedule of administration. In fac t, the sequence lonidamine->hyperthermia made the cells less sensitive to heat so that the pre-established end-point, i.e. 30% survival, was never achieved whichever combination was used. This ''drug-induced he at resistance'' was not associated with the induction of heat shock pr oteins, but rather with modification of cell cycle. On the contrary, s howing a purely additive effect, the sequence hyperthermia->lonidamine allowed achievement of the pre-established cell killing (70%), with e xposure times (1-2 hr) and with a temperature (42-degrees-C) generally accepted as clinically achievable. Therefore, also considering its lo w systemic toxicity, lonidamine may be useful in reducing the side eff ects of hyperthermia.