SCHEDULE-DEPENDENT MODULATION OF IDARUBICIN CYTOTOXICITY BY LONIDAMINE IN HUMAN LYMPHOMA CELL-LINES

The ability of lonidamine (LND), an energolytic derivative of indazol- carboxylic acid, to modulate the cytotoxic activity of idarubicin (IDA ) and doxorubicin (DX) was investigated in two human lymphoma cell lin es (H9 and U937). A different pattern of interaction between the drugs was observed as a function of treatment sequence. Specifically, a 24- h postincubation with a non-cytotoxic concentration of LND (75 mu M) i ncreased the activity of a 1-h anthracycline treatment in both cell li nes. However, the extent of potentiation for IDA was more than twofold that of DX. No enhancement of anthracycline activity was observed whe n LND preceded IDA. For comparative purposes, the modulating effect of all-trans-retinoic acid (ATRA) on the cytotoxicity of IDA was evaluat ed according to different treatment schemes in both lymphoma cell line s. In U937 cells, which undergo monocytic differentiation after exposu re to retinoids, a marked increase in LDA activity was obtained follow ing a 48-h postincubation with 1.5 mu M ATRA. No potentiation of anthr acycline activity was obtained using the opposite drug sequence. In H9 cells, no significant interference between ATRA and IDA was observed independent of the modality of drug administration. The ability of LND to potentiate IDA activity, and the consideration that LND causes sid e effects different from those caused by anthracyclines, make this com pound an attractive candidate for multidrug combination therapy in hem atological neoplasms.