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

Abstract

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 (5 microM) was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5 microM). 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 (0.5-10 microM) 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 MDR in vitro and in vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.

Multidrug resistance circumvention by a new triazinoaminopiperidine derivative S9788 in vitro: definition of the optimal schedule and comparison with verapamil

“…It induces a dose-dependent increase in doxorubicin (DOX) accumulation. It is twice as active and approximately seven times more potent than verapamil Pierre et al, 1992). In vivo, S9788 restored the anti-tumour activity of vincristine in a dosedependent manner in the P388/VCR leukaemia model (Cros et al, 1992).…”

1-Oxo-2-hydroxy-1,2-dihydroacronycine: A Useful Synthon in the Acronycine Series for the Introduction of Amino Substituents at 6-Position and for the Conversion into Isoproplfuroacridones.

“…18) The results (IC 50 ) are summarized in Table 1. The new compounds exhibited moderate cytotoxic activity, which is in agreement with our previous hypothesis that cytotoxicity in this series is correlated with the presence of a good leaving group at the benzylic position, able to ensure sufficient reactivity toward nucleophilic agents.…”

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

“…Efficacy of S9788 in reversing anthracycline resistance was also shown in vivo in animal models [24]. In a murine leukemia model resistant to anthracyclines, intraperitoneal injection of S9788 30 minutes before administration of doxorubicin resulted in significant antitumor activity [25]. Similarly, this effect could also be demonstrated with vincristine with even greater antitumor activity enhancement in the same model.…”