Pollack I F, Kawecki S, Lazo J S
Department of Neurosurgery, University of Pittsburgh School of Medicine, Pennsylvania, USA.
J Neurosurg. 1996 Jun;84(6):1024-32. doi: 10.3171/jns.1996.84.6.1024.
Seven-hydroxystaurosporine (UCN-01) is a derivative of the nonselective protein kinase inhibitor staurosporine that exhibits significant selectivity for protein kinase C (PKC) in comparison to a variety of other intracellular kinases and appears to be well tolerated in vivo at concentrations sufficient to achieve effective inhibition of PKC. Because recent studies have indicated that the proliferation of malignant gliomas may result from activation of PKC-mediated pathways and, conversely, may be inhibited by blocking PKC, the authors examined the efficacy of this agent as an inhibitor of proliferation in three established and three low-passage malignant glioma cell lines in vitro. A striking inhibition of proliferation was produced by UCN-01 in each of the cell lines, with a median effective concentration of 20 to 100 nM, which correlated with the median in vitro PKC inhibitory concentration of 20 to 60 nM for this agent in the U-87 and SG-388 glioma cell lines. Inhibition-recovery studies of clonogenic activity indicated that UCN-01 had both cytostatic and cytotoxic effects on the treated cells. Proliferation resumed after short-term (6- and 24-hour) exposures to this agent; in contrast, with longer exposures, recovery of proliferative activity was severely compromised. In addition, UCN-01 enhanced the inhibition of glioma cell proliferation achieved with conventional chemotherapeutic agents, exhibiting synergistic effects with cisplatin and additive effects with 1,3-bis(2-chloroethyl)-1-nitrosourea. In vivo studies in which UCN-01 was administered by continuous intraperitoneal infusion in subcutaneous and intracranial intraparenchymal nude rat models demonstrated significant activity against U-87 glioma xenografts at dose levels that were well tolerated. It is concluded that UCN-01 is an effective agent for the inhibition of glioma proliferation in vitro and in vivo and has potential for clinical applicability in the treatment of human gliomas.
7-羟基星孢菌素（UCN-01）是一种非选择性蛋白激酶抑制剂星孢菌素的衍生物，与多种其他细胞内激酶相比，它对蛋白激酶C（PKC）具有显著的选择性，并且在足以有效抑制PKC的浓度下，在体内似乎具有良好的耐受性。由于最近的研究表明，恶性胶质瘤的增殖可能源于PKC介导的信号通路的激活，相反，阻断PKC可能会抑制其增殖，因此作者在体外研究了该药物作为三种已建立的和三种低传代恶性胶质瘤细胞系增殖抑制剂的疗效。UCN-01在每种细胞系中均产生了显著的增殖抑制作用，中位有效浓度为20至100 nM，这与该药物在U-87和SG-388胶质瘤细胞系中的体外PKC抑制中位浓度20至60 nM相关。克隆形成活性的抑制-恢复研究表明，UCN-01对处理过的细胞具有细胞抑制和细胞毒性作用。短期（6小时和24小时）接触该药物后增殖恢复；相反，接触时间延长，增殖活性的恢复则受到严重损害。此外，UCN-01增强了传统化疗药物对胶质瘤细胞增殖的抑制作用，与顺铂表现出协同作用，与1,3-双（2-氯乙基）-1-亚硝基脲表现出相加作用。在皮下和颅内实质内裸鼠模型中通过连续腹腔内输注给予UCN-01的体内研究表明，在耐受性良好的剂量水平下，对U-87胶质瘤异种移植瘤具有显著活性。得出的结论是，UCN-01是一种在体外和体内抑制胶质瘤增殖的有效药物，在治疗人类胶质瘤方面具有临床应用潜力。
