Combined 4-hydroxy-ifosfamide and vinorelbine treatment in established and primary human breast cell cultures

Background: Vinorelbine and ifosfamide are active drugs against breast cancer, but the best treatment schedule has yet to be defined by preclinical or clinical studies. The antitumor activity of 4-hydroxy-ifosfamide (4-OH- IF), the active form of ifosfamide, and vinorelbine (VNB) and their interaction were investigated in two established breast cancer cell lines (MCF-7 and BRC-230) and in 10 primary breast cancer cultures. Materials and methods: Cytotoxic activity was evaluated by a highly efficient clonogenic assay (HECA). The median-effect principle was applied to evaluate synergistic and antagonistic interactions and the corresponding combination index values were calculated. Cell cycle perturbations were analyzed by flow cytometry. Results: In MCF-7 and BRC-230 cell lines the sequence VNB for 4 hours followed by 4-OH-IF for 24 hours produced an antagonistic effect. Conversely, the inverse sequential scheme, 4-OH-IF → VNB provided synergistic effects on both cell lines. The synergism was associated with a strong block in the G2-M phase. Synergistic activity of 4-OH-IF → VNB sequence was confirmed in 7 of 10 primary breast cancer cultures. Conclusions: In conclusion, the sequence 4-OH-IF → VNB appeared to be the most effective scheme both in established cell lines and in primary breast cancer cultures.