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Effect of 7-hydroxystaurosporine on glioblastoma cell invasion and migration

Acta Pharmacologica Sinica 2005年第4期26卷 492-499页

作者： Qing-hui MENG~2 Li-xin ZHOU~3 Jia-lin LUO~4 Jian-ping CAO~4 Jian TONG~4 Sai-jun FAN~(2,4,5) 2 Department of Oncology, Lombardi Comprehensive Caneer Center,Georgetown University,Washington DC 20057,USA 3 Institute of Medicine and Biotechnology,Chinese Academy of Medical Sciences,Beijing 100050,China 4 School of Radiation Medicine and Public Health,Soochow University,Suzhou 215007,China Department of Oncology Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA Institute of Medicine and Biotechnology Chinese Academy of Medical Sciences Beijing China School of Radiation Medicine and Public Health Soochow University Suzhou China

Aim:To investigate the effect of 7-hydroxystaurosporine（UCN-01）,a selectiveprotein kinase C（PKC）inhibitor,on cell growth,migration,and invasion in inva-sive human glioblastoma U-87MG ***:PKC activity was determinedbased on the PKC-catalyzed transfer of the32p-phosphate group from[g-32p]ATPinto a PKC-specific peptide *** viability was measured by MTT *** invasion and migration were evaluated by a Boyden chamber assay andscratch wound assay,*** expression was analyzed using West-ern blot *** formation of 3-dimensional cellular aggregates was examinedby a cell-cell aggregation ***:UCN-01 treatment resulted in concen-tration-and time-dependent inhibition of U-87MG cell growth at higher doses（>100 nmol/L）,and reduced cell invasion and migration capability at less cytotoxicdoses（<100 nmol/L）.UCN-01 significantly repressed PKC *** this result,UCN-01 blocked cell invasion stimulated by phorbel 12-myristate-13-acetate（PMA）and ethanol（EtOH）,2 PKC *** expression ofthe tumor suppressor genes BRCA1 and PTEN increased the anti-invasion poten-tial of *** to UCN-01 caused a dose-dependent increase in celladhesion molecule *** effect of UCN-01 on the formation of cell-cellaggregation was significantly reduced by the addition of an ***:UCN-01 inhibits the invasion and migration of humanglioma ***,UCN-01 can have potential clinical applications for thetreatment of human glioma metastasis.

关键词： 7-hydroxystaurosporine protein kinase C cell movement cadherins BRCA1 protein

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7-hydroxystaurosporine:一种有广泛前景的抗肿瘤药物(英文)

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中国临床药理学与治疗学 2001年第1期6卷 81-87页

作者：樊赛军孟庆慧 Laboratory of Molecular Oncology

7_hydroxystaurosporine是一种激活enzymeC类型选择性抑制剂。大量体内外实验已经证实UCN_01是一种有效的新抗肿瘤药物 ,包括抑制肿瘤的生长 ,阻断肿瘤细胞生长周期 ,导致肿瘤细胞凋亡 ,抑制肿瘤浸润和转移等。在美国和日本UCN_01已经... 详细信息

7_hydroxystaurosporine是一种激活enzymeC类型选择性抑制剂。大量体内外实验已经证实UCN_01是一种有效的新抗肿瘤药物 ,包括抑制肿瘤的生长 ,阻断肿瘤细胞生长周期 ,导致肿瘤细胞凋亡 ,抑制肿瘤浸润和转移等。在美国和日本UCN_01已经进入临床试验阶段。这篇综述总结了有关UCN_01抗肿瘤研究的文献。

关键词： 7-hydroxystaurosporine 抗肿瘤药物临床应用

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Population Pharmacokinetics of UCN-01

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Journal of Cancer Therapy 2013年第10期4卷 1513-1519页

作者： Charlene A. Baksh Martin J. Edelman Edward A. Sausville William D. Figg Hao Zhu Kenneth S. Bauer Clinical Pharmacology Research Core National Cancer Institute National Institutes of Health Bethesda USA Department of Pharmacy Practice and Science University of Maryland Baltimore School of Pharmacy Baltimore USA Office of Clinical Pharmacology Food and Drug Administration Silver Spring USA University of Maryland Greenbaum Cancer Center Baltimore USA

UCN-01 (7-hydroxystaurosporine) is an investigational anticancer agent that is currently being evaluated as targeted therapy in phase II clinical studies. The aims of this work were to describe the population pharmacokinetics of UCN-01 in patients with advanced solid tumors, and to identify covariates in patients with advanced solid tumors that affected the pharmacokinetic parameters of UCN-01. The utility of performing this research is to provide optimization of treatment and individualized dose therapy for minimization of toxicity. So, in addition to elucidating the population pharmacokinetic parameter estimates from a Phase I trial where UCN-01 was given in combination with carboplatin in patients with advanced solid tumors, and a trial where the drug was given alone as a 72-hour infusion in the same type of population, a covariate analysis was performed in order to identify pharmacokinetic determinants of UCN-01. Using NONMEM to perform nonlinear mixed-effects modeling, a linear two-compartment model was found to provide the best fit for UCN-01 data. A meta-analysis was performed, which included pooled 3-hour and 72-hour infusion data, and provided population pharmacokinetic estimates for CL (0.0157 L/hr [6.1%RSE]), V1 (2.51 L [10.0% RSE]), Q (4.05 L/hr [14.3% RSE]), and V2 (8.39 L [6.6% RSE]). Inter-individual variability was found for each of the main pharmacokinetic parameters to be ETACL (44.9% [20.8% RSE]), ETAV1 (43.9% [39.8% RSE]), ETAQ (6.09% [62.5% RSE]), and ETAV2 (4.17% [30.0% RSE]). Body surface area was found to be a statistically-significant variable from one of the individual study analyses (3-hour infusion). Population PK modeling has contributed to a better understanding of the clinical pharmacology of UCN-01. Dose individualization may improve treatment with UCN-01. Further clinical development may be supported by optimization of combination chemotherapy.

关键词： Pharmacokinetics UCN-01 7-hydroxystaurosporine Pharmacometrics Population Modeling Phase I Clinical Pharmacology

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