Abstract:
OBJECT:Recurrent malignant gliomas have inherent resistance to traditional chemotherapy. Novel therapies target specific molecular mechanisms involved in abnormal signaling and resistance to apoptosis. The proteasome is a key regulator of multiple cellular functions, and its inhibition in malignant astrocytic lines causes cell growth arrest and apoptotic cell death. The proteasome inhibitor bortezomib was reported to have very good in vitro activity against malignant glioma cell lines, with modest activity in animal models as well as in clinical trials as a single agent. In this paper, the authors describe the multiple effects of bortezomib in both in vitro and in vivo glioma models and offer a novel explanation for its seeming lack of activity. METHODS:Glioma stem-like cells (GSCs) were obtained from resected glioblastomas (GBMs) at surgery and expanded in culture. Stable glioma cell lines (U21 and D54) as well as temozolomide (TMZ)-resistant glioma cells derived from U251 and D54-MG were also cultured. GSCs from 2 different tumors, as well as D54 and U251 cells, were treated with bortezomib, and the effect of the drug was measured using an XTT cell viability assay. The activity of bortezomib was then determined in D54-MG and/or U251 cells using apoptosis analysis as well as caspase-3 activity and proteasome activity measurements. Human glioma xenograft models were created in nude mice by subcutaneous injection. Bevacizumab was administered via intraperitoneal injection at a dose of 5 mg/kg daily. Bortezomib was administered by intraperitoneal injection 1 hour after bevacizumab administration in doses of at a dose of 0.35 mg/kg on days 1, 4, 8, and 11 every 21 days. Tumors were measured twice weekly. RESULTS:Bortezomib induced caspase-3 activation and apoptotic cell death in stable glioma cell lines and in glioma stem-like cells (GSCs) derived from malignant tumor specimens Furthermore, TMZ-resistant glioma cell lines retained susceptibility to the proteasome inhibition. The bortezomib activity was directly proportional with the cells' baseline proteasome activity. The proteasome inhibition stimulated both hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) production in malignant GSCs. As such, the VEGF produced by GSCs stimulated endothelial cell growth, an effect that could be prevented by the addition of bevacizumab (VEGF antibody) to the media. Similarly, administration of bortezomib and bevacizumab to athymic mice carrying subcutaneous malignant glioma xenografts resulted in greater tumor inhibition and greater improvement in survival than administration of either drug alone. These data indicate that simultaneous proteasome inhibition and VEGF blockade offer increased benefit as a strategy for malignant glioma therapy. CONCLUSIONS:The results of this study indicate that combination therapies based on bortezomib and bevacizumab might offer an increased benefit when the two agents are used in combination. These drugs have a complementary mechanism of action and therefore can be used together to treat TMZ-resistant malignant gliomas.
journal_name
J Neurosurgjournal_title
Journal of neurosurgeryauthors
Bota DA,Alexandru D,Keir ST,Bigner D,Vredenburgh J,Friedman HSdoi
10.3171/2013.7.JNS1323subject
Has Abstractpub_date
2013-12-01 00:00:00pages
1415-23issue
6eissn
0022-3085issn
1933-0693journal_volume
119pub_type
杂志文章abstract:OBJECT:Bone morphogenetic proteins (BMPs) have been shown to have significant osteoinductive activity in numerous in vitro and in vivo assay systems, and BMP-2 and BMP-7 are currently being evaluated in human clinical studies. In the spinal region, BMPs have been shown to promote spinal arthrodesis at a higher rate tha...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/spi.2000.92.2.0191
更新日期:2000-04-01 00:00:00
abstract::Dose responses in vitro of the basilar arteries of the dog, rabbit, and man to human hemoglobin and reported. For each species, the response occurred over a range of 10(-9)M to greater than 10(-5)M hemoglobin. When compared to a maximum serotonin contraction, the relative constriction induced by 10(-5)M hemoglobin was...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1980.53.4.0486
更新日期:1980-10-01 00:00:00
abstract:OBJECTIVE:Craniopharyngiomas are rare and benign tumors of the sellar and/or parasellar region. Primary treatment involves resection followed by adjuvant radiotherapy. While the grade of resection was frequently analyzed following surgery, the neurological outcome and especially neuropsychological deficits and quality ...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2018.10.JNS181557
更新日期:2019-04-19 00:00:00
abstract::The intracranial pressure-volume (PV) relationship was examined postoperatively after removal of brain tumors in two groups of patients (13 in all). Changes of ventricular fluid pressure were analyzed by a method involving fluid injection into the lateral ventricle. A technique has been developed which provides quanti...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1982.57.4.0500
更新日期:1982-10-01 00:00:00
abstract::The outcome following decompressive laminectomy and spinal irradiation has been evaluated in 104 consecutive patients with epidural metastatic neoplasia, using broad criteria for successful outcome. Of patients so treated, 33% were benefited, while 23% became worse. Both tumor histology and the preoperative neurologic...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1980.52.1.0047
更新日期:1980-01-01 00:00:00
abstract::A case is presented of tentorial dural arteriovenous malformation (AVM) associated with visual hallucinations and quadrant hemianopsia. Computerized tomography (CT) and magnetic resonance imaging showed an ischemic region, mainly affecting the white matter of the right occipital lobe, that was defined as an area of in...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1994.80.3.0552
更新日期:1994-03-01 00:00:00
abstract::Surgical treatments for moyamoya disease (MMD) include direct revascularization procedures with proven efficacy, for example, superficial temporal artery (STA) to middle cerebral artery (MCA) bypass, STA to anterior cerebral artery bypass, occipital artery (OA) to MCA bypass, or OA to posterior cerebral artery bypass....
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2019.5.JNS19173
更新日期:2019-08-23 00:00:00
abstract::OBJECTIVE Dysfunction of distributed neural networks underlies many brain disorders. The development of neuromodulation therapies depends on a better understanding of these networks. Invasive human brain recordings have a favorable temporal and spatial resolution for the analysis of network phenomena but have generall...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2016.11.JNS161162
更新日期:2018-02-01 00:00:00
abstract::OBJECTIVESince the first clinical application of the incisionless magnetic resonance-guided focused ultrasound (MRgFUS) technology only small series of patients have been reported, and thus only extrapolations of the procedure-related risks could be offered. In this study, the authors analyze side-effects and targetin...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2017.12.JNS172054
更新日期:2018-05-01 00:00:00
abstract::The authors studied 31 comatose head-injured patients to assess the clinical usefulness of laser Doppler flowmetry (LDF) in continuous autoregulation monitoring. The LDF probes were placed on the surface of the cerebral cortex. Data on LDF, intracranial pressure (ICP), and arterial blood pressure (ABP) were recorded a...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1997.86.3.0438
更新日期:1997-03-01 00:00:00
abstract::In vivo experiments on the vasoactive effects of vasopressin and oxytocin on cerebral circulation were carried out in anesthetized dogs, using an electromagnetic flowmeter to measure vertebral blood flow and angiography to measure the internal diameter of the basilar artery. Direct bolus infusion of 1 pmol to 1 nmol o...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1992.77.3.0424
更新日期:1992-09-01 00:00:00
abstract::The fibrinolytic activity in cerebrospinal fluid has been monitored by determination of levels of fibrin split products (FSP) in 23 patients with ruptured intracranial aneurysms. In 20 of these 23, FSP was found in the cerebrospinal fluid (CSF), with levels ranging from 10 to 80 micrograms/ml. Eleven of the 23 patient...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1980.52.4.0453
更新日期:1980-04-01 00:00:00
abstract:OBJECT:The cerebellomedullary fissure (CMF) is a space between the cerebellum and the medulla oblongata, which often adhere to each other. The purpose of the present study was to demonstrate the importance of the unilateral CMF dissection for clipping vertebral artery (VA)-posterior inferior cerebellar artery (PICA) an...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2012.10.JNS12603
更新日期:2013-02-01 00:00:00
abstract::In a study examining the possible therapeutic effects of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) on malignant gliomas without expression of tumor necrosis factor (TNF)-receptors, RG-2 glioma cells were tested in vitro as well as in a rat experimental glioma model. A growth inhibition assay reveale...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1991.75.4.0597
更新日期:1991-10-01 00:00:00
abstract::This article describes a new flexible bipolar neuroelectrode which is inserted percutaneously into the epidural space for segmental spinal cord stimulation. This electrode was used in experiments with dogs and monkeys for recording cortical somatosensory evoked potentials in order to identify intraoperative spinal cor...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1984.60.6.1317
更新日期:1984-06-01 00:00:00
abstract::The authors retrospectively reviewed the surgical outcomes in 10 cases of symptomatic intradural extramedullary spinal metastases of nonneurogenic origin because the collective experience in treating this rare manifestation of systemic cancer is limited. Pain and weakness were the presenting complaints in 70% of the p...
journal_title:Journal of neurosurgery
pub_type: 杂志文章,评审
doi:10.3171/jns.1996.85.2.0225
更新日期:1996-08-01 00:00:00
abstract:OBJECTIVE:The object of this retrospective study was to investigate the impact of targeted therapies on overall survival (OS), distant intracranial failure, local failure, and radiation necrosis among patients treated with radiation therapy for renal cell carcinoma (RCC) metastases to the brain. METHODS:All patients d...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2018.8.JNS182100
更新日期:2019-01-18 00:00:00
abstract::The authors determined the landmarks and coordinates for intraoperative ventricular puncture directly from the supraorbital craniotomy opening via an eyebrow incision. Fifty magnetic resonance (MR) imaging studies were obtained from patients with no pathological cerebral characteristics or ventricular distortion. The ...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.2006.105.3.485
更新日期:2006-09-01 00:00:00
abstract:OBJECT:Operative intervention for craniovertebral junction (CVJ) instability in patients with Down syndrome has become controversial, with reports of a low incidence of associated neurological dysfunction and high surgical morbidity rates. The authors analyzed their experience in light of these poor results and attempt...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/spi.2000.93.2.0205
更新日期:2000-10-01 00:00:00
abstract:OBJECT:The aim of this study was to compare the outcomes following macrodiscectomy and microsurgery for one-level one-sided lumbar disc excision. METHODS:The authors prospectively studied 114 consecutive patients who underwent microdiscectomy (Group A, 63 patients [36 men, 27 women]) and macrodiscectomy (Group B, 51 p...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/spi.2003.99.3.0247
更新日期:2003-10-01 00:00:00
abstract:OBJECT:Factors determining choice of an academic career in neurological surgery are unclear. This study seeks to evaluate the graduates of medical schools and US residency programs to determine those programs that produce a high number of graduates remaining within academic programs and the contribution of these gradua...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2011.3.JNS101176
更新日期:2011-08-01 00:00:00
abstract::In patients with hemifacial spasm, it has been said that the spasm is due to cross compression of the facial nerve by a blood vessel and that microvascular decompression (MVD) of the facial nerve is an effective treatment. The F waves, which result from backfiring of antidromically activated motor neurons of the facia...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1997.86.4.0654
更新日期:1997-04-01 00:00:00
abstract::The T-13 spinal cord segment of dogs was compressed both acutely and chronically by means of a balloon catheter. The vascular permeability to protein was assessed using Evans blue albumin (EBA), and the dorsal column evoked potential recorded to monitor conduction failure. With acute compression sufficient to cause co...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1975.42.2.0155
更新日期:1975-02-01 00:00:00
abstract::Five full-term neonates with a posterior fossa subdural hematoma caused by birth injury are reported. All of the patients were successfully treated with surgery. They all presented with biphasic ventricular dilatation as demonstrated by serial computerized tomography (CT) scanning. The initial dilatation due to obstru...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1988.68.2.0211
更新日期:1988-02-01 00:00:00
abstract::Although severe hypovolemia can lead to hypotension and neurological decline, many patients with neurosurgical disorders experience a significant hypovolemia while autonomic compensatory mechanisms maintain a normal blood pressure. To assess the effects of normotensive hypovolemia upon cerebral hemodynamics, transcran...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1992.76.6.0961
更新日期:1992-06-01 00:00:00
abstract::An anatomical study of three microsurgical intraorbital routes to the optic nerve and orbital apex, which can be reached through a fronto-orbital craniotomy, was conducted on cadaver specimens. The structures that could be exposed via the medial, central, or lateral approaches directed through the orbital roof were de...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1994.81.1.0078
更新日期:1994-07-01 00:00:00
abstract::OBJECTIVEDifferent CSF diversion procedures (ventriculoperitoneal, ventriculoatrial, and lumboperitoneal shunting) have been utilized for the treatment of idiopathic normal pressure hydrocephalus. More recently, endoscopic third ventriculostomy has been suggested as a reasonable alternative in some studies. The purpos...
journal_title:Journal of neurosurgery
pub_type: 杂志文章,评审
doi:10.3171/2018.5.JNS1875
更新日期:2018-11-01 00:00:00
abstract::A case of brain-stem ganglioglioma is reported. A review of the literature revealed only 13 other reported cases. Brain-stem gangliogliomas usually become symptomatic in the first and second decades of life and involve the medulla and pons. Clinical improvement and prolonged survival have been reported after partial r...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/jns.1984.60.2.0431
更新日期:1984-02-01 00:00:00
abstract:OBJECT:The authors undertook this study to identify predictors of persistent postoperative seizures in their group of 28 Dutch pediatric and adolescent patients with medically intractable epilepsy who underwent functional hemispherectomy. METHODS:The records of 28 pediatric and adolescent patients who underwent a func...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/PED-07/10/275
更新日期:2007-10-01 00:00:00
abstract:OBJECTIVE:The optimal margin size in postoperative stereotactic radiosurgery (SRS) for brain metastases is unknown. Herein, the authors investigated the effect of SRS planning target volume (PTV) margin on local recurrence and symptomatic radiation necrosis postoperatively. METHODS:Records of patients who received pos...
journal_title:Journal of neurosurgery
pub_type: 杂志文章
doi:10.3171/2017.9.JNS171735
更新日期:2018-04-20 00:00:00