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.


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 analysed 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.
Ricotti
L
L
Department of Medical Oncology, G. B. Morgagni-L. Pierantoni Hospital, Forli, Italy.
Barzanti
F
F
Tesei
A
A
Amadori
D
D
Gasperi-Campani
A
A
Frassineti
G L
GL
Zoli
W
W
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D000077235:Vinorelbine; D007069:Ifosfamide