MODULATION BY LONIDAMINE ON THE COMBINED ACTIVITY OF CISPLATIN AND EPIDOXORUBICIN IN HUMAN BREAST-CANCER CELLS

The ability of lonidamine (LND), an energolytic derivative of indazole -carboxylic acid, to modulate the cytotoxic activity of cisplatin (CDD P) and epidoxorubicin (EPI), singly or in combination, was investigate d in two human breast cancer cell lines (MCF7 and T47D). A 72-hr post- incubation with a non-cytotoxic concentration of LND (75 mu M) increas ed the activity of a 1-hr CDDP treatment as well as that of al to 16-h r EPI treatment. A different pattern of interaction among the drugs an d modulator was observed as a function of the sequence of drug treatme nt. Specifically, supra-additive or additive effects of the combinatio n were obtained in the two cell lines according to the different treat ment schemes. In particular, the maximum potentiation was observed in MCF7 cells simultaneously exposed to CDDP, EPI and LND for 1 hr and th en post-incubated with LND for 72 hr, and in T47 first exposed to EPI and LND, then to CDDP and LND, and finally post-incubated with LND. Fl ow cytometric analysis of MCF7 cell distribution in the different cycl e phases showed that combined treatment with EPI/CDDP/LND was able to stabilize cell cycle perturbations (mainly G(2)M accumulation) induced by individual agents. The ability of LND to potentiate CDDP and EPI c ytotoxicity, and the consideration that LND causes side effects differ ent from those caused by alkylating agents and anthracyclines, make th is compound an attractive candidate for multidrug combination therapy in breast cancer.