INVITRO ACTIVITY OF S9788 ON MDR CELL-LINES

S9788, a new triazinoaminopiperidine derivative, was 250-fold more act ive than verapamil in sensitizing DC-3F/AD cells to actinomycin D. Thi s multidrug-resistance modulating activity of S9788 was confirmed on D C-3F/AD, P388/ADR-10, P388/VCR-20, KB/A], K562/R, S1/tMDR, and COL0320 DM cells, with respect to actinomycin D, doxorubicin, vincristine, vin blastine and etoposide. S9788 is 2-255-fold more active than verapamil , depending on the cell line and the cytotoxic agent used, potentiatin g preferentially the cytotoxicity of the vinca-alkaloid derivatives. S 9788 only had a slight effect on vincristine accumulation and retentio n by parental sensitive cells, as well as on their sensitivity to cyto toxic drugs. S9788 fully restored vincristine accumulation and retenti on by S1/tMDR cells (S] cells transfected by the mdr 1 gene) to a leve l similar to that measured in S1 cells, leading to a blockade in the G 2 + M phase of the cell cycle. Therefore, S9788 enhances vincristine a ctivity by restoring its cellular accumulation in resistant cells. Aft er a short incubation period of cells with vincristine (4 h), a condit ion close to the clinical administration of this cytotoxic agent, a po st-incubation for 20 hours more with 5 muM S9788, fully restored the s ensitivity of S1/tMDR cells to vincristine. After an exposure of 4 hou rs at equal concentrations, the accumulation of S9788 was 13-fold that of verapamil in S1/tMDR cells, and 20 hours after the removal of the modulators, S9788 was retained at a concentration 20-fold that of vera pamil. S9788 is therefore a powerful new modifier of the P-gp-mediated multidrug-resistance, which by its pharmacological properties (cellul ar kinetics and activity), might be used in combination with existing chemotherapy against tumors displaying the MDR phenotype.