识别、描述和强有力的抗肿瘤活性的eco - 4601,一本小说外围苯二氮受体配体。

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Gourdeau H,麦艾尔派恩JB,骑警M, Simard B,伯杰F, F德里,Farnet厘米,Falardeau P

识别、描述和强有力的抗肿瘤活性的eco - 4601,一本小说外围苯二氮受体配体。

癌症Chemother杂志。2008年5月,61(6):911 - 21所示。Epub 2007年7月11日。

PubMed ID

17622531 (在PubMed

]

文摘

目的:eco - 4601是一种结构新颖的farnesylated dibenzodiazepinone通过破译技术,发现Thallion专有的药物发现平台。所示的化合物有一个广泛的细胞毒性低的微摩尔的活动范围测试时NCI 60细胞系面板。在本文的工作中,eco - 4601对脑部肿瘤细胞系进一步评估。初步的机械的研究以及体内抗肿瘤进行了评价。方法:因为eco - 4601有一个benzodiazepinone一部分,我们首先研究了如果它结合中央和/或外围苯二氮受体。eco - 4601测试在放射性配体结合试验得到的苯二氮受体鼠心。eco - 4601的抑制中枢神经系统癌症的生长是评估一组老鼠,老鼠和人类神经胶质瘤细胞系使用MTT试验标准。抗肿瘤功效研究进行神经胶质瘤(大鼠和人类),人类乳腺癌和前列腺癌小鼠肿瘤异种移植。eco - 4601的抗肿瘤活性和药代动力学分析是评估静脉(注射)后,皮下(南),和腹腔内(i.p)丸政府。结果:eco - 4601显示绑定外围但不是中央苯二氮受体和抑制中枢神经系统肿瘤细胞系的生长。 Bolus s.c. and i.p. administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, i.v. dosing was followed by rapid elimination of the drug and was ineffective. CONCLUSIONS: Antitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained drug levels rather than C (max). These in vivo data constitute a rationale for clinical studies testing prolonged continuous administration of ECO-4601.

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药物

Diazepinomicin