SCHEDULE-DEPENDENT SYNERGISM OF TAXOL OR TAXOTERE WITH EDATREXATE AGAINST HUMAN BREAST-CANCER CELLS IN-VITRO

A new dihydrofolate reductase inhibitor, edatrexate (EDX, and the micr otubule polymerization promotor, taxol (TXL) or taxotere (TXT), each h ave significant therapeutic activity against human breast cancer in cl inical trials. Since they also have distinctly different mechanisms of actions and have mainly nonoverlapping toxicities, they may be effect ive in combination in the treatment of this disorder. Schedule-depende nt interactions between these taxanes and EDX against human breast ade nocarcinoma cells (SK-Br-3) were quantitatively assessed in vitro to d etermine whether these interactions are synergistic or antagonistic. S K-Br-3 cells were grown as a monolayer in 96-well microplates. The dos e-effect relationships of the drugs, singly and in combination, in inh ibiting the growth over a 7-day period were determined by the SRB prot ein staining assays. Cell cultures were exposed to drug as a 3-h pulse at either 0-3 h or 24-27 h. Synergism or antagonism at different conc entrations and at different effect levels were assessed with the media neffect principle and the combination index-isobologram method using c omputer software. These methods were selected because they take into a ccount both the potencies and the shape of the dose-effect curves. Exp osure of cells to an equimolar combination of EDX + TXL (0-3 h) result ed in synergism at high effect levels. Pretreatment of cells with EDX (0-3 h) followed by TXL (24-27 h) showed even greater synergism in inh ibiting cell growth. Moderate antagonism was observed with the reverse schedule. EDX + TXT (0-3 h) was additive, but pretreatment with EDX ( 0-3 hr) followed by TXT (24-27 h) showed synergism. However, the rever se order showed antagonism. Studies on another breast tumor cell line, ZR-57-1, also showed the schedule of EDX (0-3 h) + TXT or TXL (24-27 h) to be more synergistic than, the other two schedules examined. Thes e results show potent schedule-dependent synergism of the combinations of TXL or TXT with EDX, and should form a rationale for designing cli nical protocols utilizing these agents particularly for the treatment of breast cancer patients.