Modulation of cytotoxic drug activity by mitotane and lonidamine in human adrenocortical carcinoma cells

The ability of mitotane, a DDT derivative with adrenotoxic activity, and lo nidamine, an energolytic derivative of indazole-carboxylic acid, to modulat e the cytotoxic activity of doxorubicin, epidoxorubicin, cisplatin and VP16 was investigated in a human adrenocortical carcinoma cell line (SW13). A m arked variability in cellular response to a l-h treatment with the individu al anticancer agents was observed. The concentrations able to inhibit SW13 cell proliferation by 50% (IC50) were 0.45 mu g/ml and 0.4 mu g/ml for doxo rubicin and epidoxorubicin, respectively, thus indicating a relative sensit ivity to anthracyclines. Conversely, the SW13 cell line displayed a marked resistance to cisplatin (IC50, 13.9 mu g/ml) and VP16 (IC50, 15 mu g/ml). W hen cells were exposed to anticancer drugs and mitotane simultaneously or i n sequence, a positive modulation of anthracycline cytotoxic effects was ob served. Although to a lesser extent, mitotane also increased cisplatin acti vity. Conversely, no potentiation was observed when mitotane was combined w ith VP16. Lonidamine slightly increased the cytotoxicity of epirubicin and cisplatin as individual agents. Moreover, a supra-additive effect of the th ree-drug (epidoxorubicin-cisplatin-lonidamine) combination was observed.