In vitro and in vivo circumvention of multidrug resistance by Servier 9788, a novel triazinoaminopiperidine derivative.
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.
Pierré
A
A
Institut de Recherches Servier, Division de Cancérologie expérimentale, Suresnes, France.
Dunn
T A
TA
Kraus-Berthier
L
L
Léonce
S
S
Saint-Dizier
D
D
Régnier
G
G
Dhainaut
A
A
Berlion
M
M
Bizzari
J P
JP
Atassi
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D005434:Flow Cytometry; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D010880:Piperidines / Q000627:therapeutic use*; D014227:Triazines / Q000627:therapeutic use*; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D010880:Piperidines; D014227:Triazines; C077022:S 9788; D014750:Vincristine; D004317:Doxorubicin