Effects of 13-hydroxy SM5887 in combination with other anticancer agents on human tumor cell lines

A new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887) and other drugs for 3 and 4 days, respectively. Cell growth inhibition was determined by MTT assay. The antitumor effects of the drug combinations at 80% inhibitory concentration (IC80) were analyzed by the isobologram of Steel and Peckham. In MOLT-3 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide, 5-fluorouracil, cytarabine, and vincristine, whereas it had mainly protective (marked antagonistic) effects with methotrexate. In MG-63 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide; mainly subadditive (mild antagonistic) effects with 5-fluorouracil and cytarabine; and mainly protective (marked antagonistic) effects with vincristine and methotrexate. These findings suggest that SM5887 is suitable for simultaneous administration with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, or ifosfamide and not suitable for simultaneous administration with methotrexate. The effects of SM5887 in combination with 5-fluorouracil, cytarabine or vincristine may be variable, depending on cell lines. To find optimal combinations, further in vitro and in vivo studies of antitumor activity and toxicity appear to be warranted.