Early prediction of response to Vorinostat in an orthotopic rat glioma model.
Early prediction of response to Vorinostat in an orthotopic rat glioma model.
复制标题
DOI：
10.1002/nbm.2776
复制
发表时间：
2012-09
影响因子：
2.9
通讯作者：
Shim, Hyunsuk
中科院分区：
文献类型：
--
作者：
Wei, Li;Hong, Samuel;Yoon, Younghyoun;Hwang, Scott N.;Park, Jaekeun C.;Zhang, Zhaobin;Olson, Jeffrey J.;Hu, Xiaoping P.;Shim, Hyunsuk
胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，尽管进行了积极的手术和辅助治疗，但仍是致命的。由于生存期短，因此在治疗早期确定治疗价值至关重要。改进的早期预测评估将允许神经肿瘤学家更快地个性化和调整或改变治疗，以最大限度地利用有效的治疗。在肿瘤发生过程中，组蛋白脱乙酰化的异常可使肿瘤抑制基因沉默。这种表观遗传修饰已成为肿瘤治疗的重要靶点。辛二酰苯胺异羟肟酸（SAHA，伏立诺他，Zolinza; Merck & Co.，公司）是一种口服有效的组蛋白脱乙酰酶（HDAC）活性抑制剂。使用HDAC抑制剂治疗脑肿瘤患者的主要缺点是缺乏可靠的生物标志物来预测和确定反应。组织学评价可以反映治疗后的肿瘤活力，但它是一种侵入性程序，对GBM不切实际。另一个问题是，对SAHA治疗的反应与肿瘤再分化和细胞停滞有关，而不是肿瘤大小减小，因此限制了传统成像方法的使用。需要一种非侵入性的方法来评估药物输送和疗效。在此，我们研究了在原位胶质瘤动物模型中，1H MRS代谢物的变化是否可以为SAHA治疗的早期反应提供可靠的生物标志物。未经治疗的肿瘤表现出显着升高的丙氨酸和乳酸盐水平和减少肌醇，NAA和肌酸，在GBM相比，正常脑组织中报告的典型变化。SAHA处理的肿瘤的质子MRS可检测的代谢物恢复到正常样脑组织的代谢物。此外，减少肌醇和NAA被发现是情绪改变和抑郁症的潜在生物标志物，这也可以通过SAHA治疗来缓解。我们的研究表明，1H MRS可以在SAHA治疗的最早阶段提供可靠的代谢生物标志物，以预测治疗反应。
Glioblastoma (GBM) is the most common primary brain tumor and is uniformly fatal despite aggressive surgical and adjuvant therapy. Since survival is short, it is critical to determine the value of therapy early on in treatment. Improved early predictive assessment would allow neuro-oncologists to personalize and adjust or change treatment sooner to maximize use of efficacious therapy. During carcinogenesis, tumor suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza; Merck & Co., Inc.) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. A major shortcoming of the use of HDAC inhibitors in treating brain tumor patients is the lack of reliable biomarkers to predict and determine response. Histological evaluation may reflect tumor viability following treatment but it is an invasive procedure and impractical for GBM. Another problem is that response to SAHA therapy is associated with tumor redifferentiation and cytostasis rather than tumor size reduction, thus limiting the use of traditional imaging methods. A noninvasive method to assess drug delivery and efficacy is needed. Here, we investigated whether changes in 1H MRS metabolites could render reliable biomarkers for an early response to SAHA treatment in an orthotopic animal model for glioma. Untreated tumors exhibited significantly elevated alanine and lactate levels and reduced inositol, NAA and creatine, typical changes reported in GBM compared to normal brain tissues. The proton MRS-detectable metabolites of SAHA treated tumors were restored toward those of normal-like brain tissues. In addition, reduced inositol and NAA were found to be potential biomarkers for mood alteration and depression, which may also be alleviated with SAHA treatment. Our study suggests that 1H MRS can provide reliable metabolic biomarkers at the earliest stage of SAHA treatment to predict the therapeutic response.
登录
查看更多内容
DOI：
10.1523/jneurosci.1758-09.2009
发表时间：
2009-09-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Covington HE 3rd;Maze I;LaPlant QC;Vialou VF;Ohnishi YN;Berton O;Fass DM;Renthal W;Rush AJ 3rd;Wu EY;Ghose S;Krishnan V;Russo SJ;Tamminga C;Haggarty SJ;Nestler EJ
通讯作者：
Nestler EJ
影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
11.2
作者：
Hsi, LC;Xi, XP;Lippman, SM
通讯作者：
Lippman, SM
影响因子：
3.3
作者：
Howe, FA;Barton, SJ;Griffiths, JR
通讯作者：
Griffiths, JR
DOI：
10.1016/j.nurt.2009.04.002
发表时间：
2009-07
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Nagarajan RP;Costello JF
通讯作者：
Costello JF