[Quantitative cytological study of the activity of a new resistance modulator, S 9788, on human leukemic cells using...

The triazinoaminopiperidine derivative S 9788 is a new multidrug resistance modulator. The modulating activity of S 9788, comparatively to those of verapamil and the combination of S 9788 and verapamil, was demonstrated on the human leukemic T cell line CCRF-CEM resistant (about 6000 fold) to vinblastine using Microculture Tetrazolium Assay. S 9788 at 5 microM, strongly potentialized the cytotoxic activity of vinblastine but the reversion of resistance remained partial. Verapamil and the combination S 9788-verapamil, tested at equimolar concentrations, were respectively 1000 and two times less active than S 9788 alone. The impact of S 9788, verapamil and their combination on the cytological modifications bound to vinblastine resistance of CEM cells was evaluated by multiparametric quantitative cytological analysis (21 nuclear parameters measured) using a SAMBA 2005 cell image processor. Treatments with the different modulators, in absence or in presence of vinblastine, had no significant effects on the morphology of sensitive CEM cells. On vinblastine resistant CEM cells, S 9788 and the combination S 9788-verapamil induced significant cytological modifications. These modifications were characterized by a partial reversion of some parameters (more specifically nuclear texture parameters) to values close to those observed in parental sensitive cells and permitted an automatic classification of these treated resistant cells in cells of "sensitive" type with a percentage superior to 50%. In conclusion, the reversion of resistance induced by S 9788 on CEM cells resistant to vinblastine does not fit only with a biological phenomenon like the efflux of cytotoxic agents but is associated with a set of cellular alterations involved in multidrug resistance.