INVITRO AND INVIVO CIRCUMVENTION OF MULTIDRUG RESISTANCE BY SERVIER-9788, A NOVEL TRIAZINOAMINOPIPERIDINE DERIVATIVE
INVITRO AND INVIVO CIRCUMVENTION OF MULTIDRUG RESISTANCE BY SERVIER-9788, A NOVEL TRIAZINOAMINOPIPERIDINE DERIVATIVE
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DOI：
10.1007/bf00877238
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发表时间：
1992-08-01
影响因子：
3.4
通讯作者：
ATASSI, G
中科院分区：
文献类型：
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作者：
PIERRE, A;DUNN, TA;ATASSI, G
S 9788 是一种新型三嗪氨基哌啶衍生物，不属于任何已知可逆转多药耐药性 (MDR) 的化合物类别。在逆转 ADR 选择的小鼠白血病细胞系 P388/ADR-1 和 P388/ADR-10 以及人类慢性粒细胞白血病 K562/R 中对阿霉素 (ADR) 的耐药性方面，S 9788 比维拉帕米 (VRP) 更有效。 S 9788 (5 muM) 的倍数回复分别是 VRP (5 muM) 的 3.5、5.4 和 11.3 倍。 S 9788 也是本质上耐药的人结肠腺癌 COLO 320DM 中 ADR 耐药性的更有效逆转剂（2.3 倍），以及人 MDR1 基因转染的鳞状肺癌细胞系 SI/tMDR1 中的长春新碱 (VCR) 耐药性的更有效逆转剂（5.6 倍）。 S 9788 的活性取决于 MDR 细胞系和细胞毒剂。在第 1-4 天每天一次腹腔注射 S 9788（50-100 mg/kg/d），导致 P388/VCR 小鼠中 VCR（0.25 mg/kg/d）和 P388/ADR 小鼠中 ADR（4 mg/kg/d）的化疗效果呈剂量依赖性增加。相对于单独的细胞毒剂治疗，P388/ADR模型中的抗肿瘤活性增加(％T/C)为+20-34％，P388/VCR模型中的抗肿瘤活性增加为+50-78％。 S 9788 在其有效剂量下似乎没有毒性。 S 9788 的作用机制尚不清楚，但 S 9788 (0.5-10 muM) 诱导 KB-A1 细胞中 ADR 积累呈剂量依赖性增加，与维拉帕米相比，其作用活性高两倍，效力高约七倍。我们得出的结论是，S 9788 是一种能够在体外和体内逆转 MDR 的新型药物，其药理学特征值得选择作为候选药物进行最终的临床评估。
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 muM) was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5 muM). 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 SI/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 muM) 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.