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nM。无论预后指标和治疗史如何,SNS-032在体外有效杀死慢性淋巴细胞白血病细胞。与flavopiridol和roscovitine相比,SNS-032在抑制RNA合成和诱导细胞凋亡方面更有效。 SNS-032活性很容易逆转;去除SNS-032重新激活RNA聚合酶II,导致Mcl-1再合成和细胞存活[1]。 SNS-032抑制内皮细胞的三维毛细血管网络形成。 SNS-032完全阻止U87MG细胞介导的HUVEC毛细血管形成。此外,SNS-032显着阻止两种细胞系中VEGF的产生,SNS-032阻止体外血管生成,并且该作用可归因于VEGF的阻断。临床前研究表明,SNS-032在多种细胞系中诱导细胞周期停滞和细胞凋亡[2]。 SNS-032通过抑制CDKs 2和7来阻断细胞周期,并通过抑制CDK 7和9来转录.SNS-032活性不受人血清的影响[3]。 SNS-032诱导膜联蛋白V染色和胱天蛋白酶-3激活的剂量依赖性增加。在分子水平上,SNS-032诱导RNA聚合酶(RNA Pol)II的丝氨酸2和5的显着去磷酸化,并抑制CDK2和CDK9的表达以及去磷酸化的CDK7 [5]。",{"key":239,"value":240},"体内研究","SNS-032(15mg\u002Fkg,ip)在体内抑制异种移植的BaF3-T674I细胞和KBM5-T315I细胞。 SNS-032通过下调T674IPDGFRα和T315I-Bcr-Abl来消除裸鼠移植肿瘤的生长[4]。",{"key":242,"value":243},"细胞实验","进行Cell Titer-Glo（CTG）发光测定以测量HUVEC和U87MG细胞的生长曲线。将U87MG细胞和HUVEC（2×103细胞\u002F孔）接种在96孔微量培养板中，最终体积为100mL。 24小时后，用不同剂量的SNS-032（0-0.5mM）处理细胞24,48或72小时。处理完成后，向各孔中加入100mL CTG溶液，在室温下避光孵育20分钟。将裂解物（50mL）转移至96孔白色板，并通过POLARstar OPTIMA测量发光。通过考虑添加SNS-032时的100％生长来计算细胞生长百分比。",{"key":245,"value":246},"动物实验","裸鼠nu \u002F nu BALB \u002F c小鼠饲养在屏障设施中，12小时光暗循环，随意提供食物和水。将1×107个BaF3-T674I细胞与基质胶或KBM5-T315I细胞（3×107）的混合物皮下接种到4-6周龄雄性裸鼠的侧腹上。每隔一天使用卡尺测量肿瘤。肿瘤体积通过下式计算：a2×b×0.4，其中a是最小直径，b是垂直于a的直径。皮下接种后4天，当肿瘤可触及（约100mm 3）时，将小鼠随机分组接受载体（含有DMSO 0.1％v \u002F v的组织培养基）或SNS-032（每2天腹腔注射15mg \u002F kg）治疗。 ）约2周。在稀释前将SNS-032溶解于组织培养级DMSO中。监测每只动物的体重，摄食行为和运动活动作为一般健康的指标。然后使动物安乐死，立即取出肿瘤异种移植物，称重，储存并固定。",{"key":248,"value":249},"参考文献","[1].\nChen R, et al. Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.\n[2].\nAli MA, et al. SNS-032 prevents tumor cell-induced angiogenesis by inhibiting vascular endothelial growth factor. Neoplasia. 2007 May;9(5):370-81.\n[3].\nConroy A, et al. SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples. Cancer Chemother Pharmacol. 2009 Sep;64(4):723-32.\n[4].\nWu Y, et al. Cyclin-dependent kinase 7\u002F9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor α and bcr-abl oncogene addiction in malignant hematologic cells.Clin Cancer Res. 2012 Apr 1;18(7):1966-78. Epub 2012 Mar 23.\n[5].\nWalsby E, et al. The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine.Leukemia. 2011 Mar;25(3):411-9. 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