MULTIDRUG-RESISTANCE CIRCUMVENTION HY A NEW TRIAZINOAMINOPIPERIDINE DERIVATIVE S9788 IN-VITRO - DEFINITION OF THE OPTIMAL SCHEDULE AND COMPARISON WITH VERAPAMIL

The current work was undertaken to investigate the importance of expos ure sequence and duration in achieving the maximum reversal action of S9788 on doxorubicin (DOX) cytotoxicity against cells that exhibit the (MDR) multidrug resistance phenotype: the MCF7/DOX cell line. Accumul ation and release of DOX were examined in this cell line. The reversal effect was compared with that obtained with verapamil. S9788 activity was schedule dependent: when comparing incubation with S9788 before o r after treatment with DOX, the best reversal factor was obtained in t he case of a post-treatment incubation (65.6 +/- 7.7 vs 20.8 +/- 7.0). S9788 was a more potent modulating agent than verapamil, whatever the schedule of exposure of the cells to the reversal agent. The reversal of resistance after short-term DOX exposures was caused not only by p rolonged cellular accumulation of DOX, but also by its prolonged reten tion after transfer of cells to DOX-free medium. A relationship was no ted between cellular exposure to DOX and the cytotoxic effect, and so the reversal of resistance induced by S9788 appears to be directly lin ked to the level of cell exposure to DOX. This work provided a rationa le for improving the schedule of administration of S9788 in clinical t rials.