In vitro andin vivo circumvention of multidrug resistance by Servier 9788, a novel triazinoaminopiperidine derivative

Abstract

Summary S 9788 is a novel triazinoaminopiperidine derivative which does not belong to any of the classes of compounds known to reverse multidrug resistance (MDR). S 9788 was far more potent than verapamil (VRP) in reversing resistance to adriamycin (ADR) in the ADR-selected murine leukaemia cell lines P388/ADR-1 and P388/ADR-10, and the human chronic myelogenous leukaemia K562/R. Fold reversion with S 9788 (5μM was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5μM). S 9788 was also a more potent reversant of ADR resistance in the intrinsically resistant human colon adenocarcinoma COLO 320DM (2.3 fold), and of vincristine (VCR) resistance in the human MDR1 gene-transfected squamous lung carcinoma line S1/tMDR1 (5.6 fold). The activity of S 9788 depended on both the MDR cell line and the cytotoxic agent. S 9788 (50–100 mg/kg/d) administered IP once a day on days 1–4 resulted in a dose-dependent increase in the chemotherapeutic effect of VCR (0.25 mg/kg/d) in P388/VCR-bearing mice and ADR (4 mg/kg/d) in P388/ADR-bearing mice. Increases in antitumor activity were (% T/C) of +20–34% in the P388/ADR model and +50–78% in the P388/VCR model with respect to cytotoxic agent treatment alone. S 9788 appeared to be devoid of toxicity at its effective doses. The mechanism of action of S 9788 is unknown but S 9788 (0.5–10μM) induced a dose-dependent increase in ADR accumulation in KB-Al cells and compared to verapamil its effect was twice as active and approximately seven times more potent. We conclude that S 9788 is a novel agent capable of reversing MDRin vitro andin vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.