IN-VITRO ACTIVITY OF S-9788 ON A MULTIDRUG-RESISTANT LEUKEMIC-CELL LINE AND ON NORMAL HEMATOPOIETIC CELLS-REVERSAL OF MULTIDRUG-RESISTANCE BY SERA FROM PHASE-I TREATED PATIENTS

The triazinoaminopiperidine derivative S 9788 is a new multidrug-resis tance modulator that is currently being evaluated in phase I clinical trials. In this study, the reversal effect of S 9788 in comparison wit h verapamil was shown in vitro in human T-leukemic CCRF-CEM/VLB cells expressing the multidrug-resistance (MDR) phenotype. S 9788 increased in a dose-dependent manner the cytotoxic activity of doxorubicin or vi nblastine, with complete reversal of resistance occurring at 2 mu M fo r a concomitant continuous exposure (96 h) to the cytotoxic drugs. At respective concentrations equivalent to the IC10 value (the concentrat ion inhibiting 10% of cell growth), S 9788 was 44 times more potent th an verapamil in CCRF-CEM/VLB cells. S 9788 at 2 mu M did not enhance t he in vitro toxicity of doxorubicin or vinblastine in the human normal bone-marrow erythroid (BFU-E) and myeloid (CFU-GM) progenitors. The e ffect of exposure duration and concentrations on the synergistic actio n of modulator and cytotoxic agent closely depended on the cytotoxic a gent studied. Post-incubations with S 9788 alone after a 1-h coadminis tration with vinblastine and S 9788 dramatically increased the reversa l effect (4-41 times) in proportion to both the duration of postincuba tion and the concentration of S 9788. In contrast, for doxorubicin res istance, postincubation with S 9788 alone induced a maximal 2-fold inc rease in the reversal effect that was not proportional to the postincu bation duration. In patients treated with S 9788 as a 30-min intraveno us infusion during phase I trials, a good correlation was found betwee n the serum levels of S 9788 and the ability to reverse MDR in CCRF-CE M/VLB eels. The reversal effect was dose-dependent and was effective b eginning at a plasma concentration of 0.25 mu M. These data form a bas is for the design of phase II trials using a combination of a loading dose of S 9788 given before vinblastine or doxorubicin administration followed by a maintenance infusion of S 9788 alone for a period of 2-2 4 h.