ATYPICAL MULTIDRUG-RESISTANCE (MDR) - LOW-SENSITIVITY OF A P-GLYCOPROTEIN-EXPRESSING HUMAN-T LYMPHOBLASTOID MDR CELL-LINE TO CLASSICAL P-GLYCOPROTEIN-DIRECTED RESISTANCE-MODULATING AGENTS

Verapamil, cyclosporin A (CsA), the cyclosporin derivative SDZ PSC 833 and the novel cyclopeptolide SDZ 280-446 were tested for their capaci ty to chemosensitize a P-glycoprotein (Pgp)-expressing multi-drug resi stant (MDR) variant of the CEM human T lymphoblastoid cell subline (CC RF ACTD 400+). That MDR-CEM cell subline had been previously selected for MDR by actinomycin D and displayed a very high resistance phenotyp e: 3700-fold for actinomycin D, 3900-fold for vincristine, 1200-fold f or taxol, 1000-fold for daunomycin (DAU) and 400-fold for colchicine. Interestingly, these MDR-CEM cells displayed little chemosensitization by resistance-modulating agents (RMA) which presumably work by inhibi ting Pgp function. These MDR-CEM cells displayed virtually no chemosen sitization by 1 muM verapamil or 1 mug/ml (about 0.8 muM) CsA, whereas their chemosensitization for different anticancer drugs (ACD) was rat her stable (from 51- to 82-fold) with 1 mug/ml (about 0.8 muM) SDZ 280 -446, while being very unbalanced (from 5- to 38-fold) with 1 mug/ml ( about 0.8 muM) SDZ PSC 833. Exposure of the MDR-CEM cells to Pgp-direc ted RMAs, during their loading with DAU (DAU-loading phase), hardly re stored DAU retention: SDZ 280-446 being as poorly active as SDZ PSC 83 3, and about only 3- and 4-fold more active than CsA and verapamil. In contrast, SDZ PSC 833 treatment of human MDR-KB and MDR-LoVo cell lin es under the same conditions could restore most or all the DAU retenti on shown by tha parental (Par) cells, in spite of their high level of resistance. By keeping the MDR-CEM cells in the presence of RMA throug hout the experiment (both DAU-loading and DAU-efflux phases), a better DAU retention could be restored by the different RMAs used, their ord er of relative restoration activity being SDZ 280-446 3- to 4-fold > S DZ PSC 833 3- to 10-fold > CsA 2- to 4-fold > verapamil. Nevertheless, the level of DAU retention restored in the MDR-CEM cells reached a pl ateau at 50% of the Par-CEM cell level. Therefore, although the MDR-CE M cells expressed easily detectable membranous Pgp molecules and proba bly used them for DAU efflux, they displayed an additional efflux mech anism that was not sensitive to the Pgp inhibitors.