Multidrug resistance circumvention by 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 exposure 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. Accumulation 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 or after treatment with DOX, the best reversal factor was obtained in the 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 prolonged cellular accumulation of DOX, but also by its prolonged retention after transfer of cells to DOX-free medium. A relationship was noted between cellular exposure to DOX and the cytotoxic effect, and so the reversal of resistance induced by S9788 appears to be directly linked to the level of cell exposure to DOX. This work provided a rationale for improving the schedule of administration of S9788 in clinical trials.