PHARMACOLOGICAL PROPERTIES OF S9788, A NEW MULTIDRUG-RESISTANCE MODULATOR

S9788, a triazinoaminopiperidine derivative, is a new multidrug resistance (MDR) modulating agent. S9788 activity was investigated on 12 tumoral cell lines, either sensitive or resistant, with respect to different cytotoxic agents: adriamycin (ADR), daunorubicin (DNR), vincristine (VCR) and vinblastine (VLB). S9788 is 1.5 to 30 times more active than verapamil and 1.2 to 119 times more active than cyclosporin, depending on both the cell line and the antitumoral agent. Reversion of resistance to ADR was nearly complete in K562R at 5 muM S9788 (F Res = 30; F Rev = 20). In MCF7/ADR cell line, highly resistant to ADR, S9788 (1 muM) partially reversed the resistance (F Res = 917; F Rev = 110). S9788, when associated with either ADR or vinca-alcaloids, had a slight effect on ovarian carcinoma (OVCCR1, NIHOVCAR3, SKOV3, IGROV1), sarcoma (SARCCR2) and breast adenocarcinoma (CAL51, CAL85-1/2) cell lines which poorly expressed P glycoprotein (F Rev = 1-3). In K562R cells, S9788 (5 muM) restored DNR accumulation (measured by flow cytometry) to a level similar to that measured in sensitive cells K562S. A novel method of microspectrofluorimetry showed that S9788 modified the kinetic and the intracellular distribution of cytotoxic agent, leading to its accumulation in resistant cell nuclei. Concomitant incubation of S9788 and cytotoxic agent, followed by a postincubation with S9788 alone, significantly increased MDR reversion. Therefore. S9788 should be used as an adjuvant of polychemotherapy against tumors displaying MDR phenotype.