SEQUENCE-DEPENDENT GROWTH-INHIBITORY EFFECTS OF THE IN-VITRO COMBINATION OF FLUOROURACIL, CISPLATIN, AND DIPYRIDAMOLE

The present study was designed to analyze the growth-inhibitory effect s of the combination of fluorouracil (FUra), cisplatin (CDDP), and dip yridamole (DP). These toxic effects were assessed on the human breast- carcinoma cell line MCF-7 using the MTT (tetrazolium bromide) assay in 96-well culture dishes. Data were analyzed using the median-effect pr inciple. The drug combinations tested included FUra concentrations ran ging from 0.8 to 800 nmol/l, CDDP concentrations of 0.3 -30 mu mol/l, and DP concentrations of 2-200 mu mol/l. A total of 189 different expe rimental conditions were tested, including different sequences of admi nistration, with being DP applied before, simultaneously with, or afte r the two antitumor drugs. Synergistic cytotoxic interactions were fou nd between FUra and CDDP, FUra and DP, and CDDP and DP as well as when the three drugs were combined. The sequence of exposure did not influ ence the growth-inhibitory activity of the combination FUra-CDDP but a ltered the effect of combinations of either FUra or CDDP with DP, sinc e at lower concentrations the effect shifted from synergism to antagon ism when DP was added simultaneously with CDDP and after the two antit umor drugs. However, the interaction was shown to be truly synergistic by median-effect analysis when the two antitumor drugs were simultane ously associated, with no change in the synergistic effect being obser ved for the three DP administration sequences.