Additive activity of mitoxantrone and doxorubicin in vitro against human breast cancer

Both doxorubicin and mitoxantrone have proved useful clinically in the treatment of metastatic breast cancer. They have not been combined in the clinic because of their overlapping myelosuppressive and cardiac toxicities; nevertheless, such use in patients would be justified it the two drugs were shown to be synergistic or even additive in their cytotoxic effects against human breast cancers. We have evaluated the combined cytotoxic effects of these two anti-cancer drugs against the MCF-7 human breast cancer cell line, using donogenic assays and isobologram and median dose-effect principle analysis. The ID₅₀ for mitoxantrone and doxorubicin was 0.058 and 0.247 μmol, respectively, against MCF-7 tumour colony forming units. Isobologram analysis revealed a line of strict additivity and the median dose-effect principle showed synergism for the combination of these two agents over a wide range of concentrations against the MCF-7 cells. We conclude that these data provide an adequate rationale for the combination of mitoxantrone with doxorubicin in phase I and II clinical trials in patients with metastatic breast cancer.