Abstract:
PURPOSE:Current medulloblastoma therapy, surgery, radiation, and chemotherapy, is unacceptably toxic. However, 13-cis retinoic acid (RA) and SAHA, a histone deacetylase inhibitor, have each been shown to induce apoptosis in medulloblastoma cultures and mouse models. Both drugs cross the blood brain barrier, have been given safely to children, and achieve brain concentrations that are at or near therapeutic levels. Retinoic acid acts by transcriptionally activating bone morphogenetic protein-2 (BMP-2) and SAHA facilitates transcriptional activity through chromatin accessibility. We tested the hypothesis that these drugs additively induce BMP-2 transcription and apoptosis. EXPERIMENTAL DESIGN:RA + SAHA induction of BMP-2 transcription and apoptosis in medulloblastoma cultures was evaluated. Subsequently the response of mouse medulloblastomas to these two agents in the presence and absence of cisplatin was evaluated. RESULTS:BMP-2 transcription multiplied 3-fold with addition of RA to culture, and 7-fold with both agents. The IC50 of SAHA was reduced by 40% when low dose RA was added. Interestingly, a p38 MAP kinase inhibitor that partially blocks RA-induced apoptosis did not inhibit the activity of RA + SAHA. Flank D283 tumors in athymic mice had slower growth in the RA + SAHA arm than single drug or control arms. Intracranial tumors in ND2:SmoA1 mice treated with RA + SAHA + cisplatin showed a 4-fold increase in apoptosis over controls, and a 2-fold increase over animals receiving only SAHA or RA + SAHA. CONCLUSIONS:RA + SAHA additively induce BMP-2 transcription and medulloblastoma apoptosis. The combination may act through a p38 MAPK independent mechanism. Efficacy increased with cisplatin, which has implications for clinical trial design.
journal_name
J Neurooncoljournal_title
Journal of neuro-oncologyauthors
Spiller SE,Ditzler SH,Pullar BJ,Olson JMdoi
10.1007/s11060-007-9505-1subject
Has Abstractpub_date
2008-04-01 00:00:00pages
133-41issue
2eissn
0167-594Xissn
1573-7373journal_volume
87pub_type
杂志文章abstract::In this retrospective, IRB-exempt study, we analyzed data from 68 patients diagnosed with glioblastoma (GBM) in two institutions and investigated the relationship between tumor shape, quantified using algorithmic analysis of magnetic resonance images, and survival. Each patient's Fluid Attenuated Inversion Recovery (F...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,多中心研究
doi:10.1007/s11060-016-2359-7
更新日期:2017-03-01 00:00:00
abstract::We examined the mechanism of action of nitrosoureas as represented by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) with respect to p53 and the G2M cell cycle checkpoint using two glioblastoma cell lines: U251MG and U373MG, with mutated p53. At log-phase cell growth, fresh medium con...
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章,meta分析
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abstract::Brain metastasis often has a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Therefore, it is urgent to identify factors associated with lung cancer brain metastasis. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) also known as noncoding nuclear-enriched abundant transcrip...
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abstract::The aim of the study was to examine associations between occupational exposure to metals and meningioma risk in the international INTEROCC study. INTEROCC is a seven-country population-based case-control study including 1906 adult meningioma cases and 5565 population controls. Incident cases were recruited between 200...
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pub_type: 杂志文章
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
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更新日期:1998-01-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
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更新日期:1998-05-01 00:00:00
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更新日期:2019-09-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-007-9426-z
更新日期:2007-12-01 00:00:00
abstract::The treatment of visual pathway gliomas is controversial. The many retrospective studies reporting outcome data for patients with chiasmatic/hypothalamic gliomas are difficult to interpret for several reasons. First the natural history of these tumors is erratic with some reports suggesting that most visual pathway gl...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/BF00250197
更新日期:1996-05-01 00:00:00
abstract:TARGET POPULATION:These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven glioblastoma (GBM). QUESTION:What are the optimal imaging techniques to be used in the management of a suspected glioblastoma (GBM), specifically: which imaging sequences are critical fo...
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pub_type: 杂志文章,评审
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更新日期:2006-09-01 00:00:00
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pub_type: 临床试验,杂志文章
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
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更新日期:1993-04-01 00:00:00
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journal_title:Journal of neuro-oncology
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更新日期:2007-06-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
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更新日期:2011-02-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/BF00165526
更新日期:1991-12-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
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更新日期:2017-05-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
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更新日期:2019-01-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-007-9411-6
更新日期:2007-12-01 00:00:00
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-015-1791-4
更新日期:2015-06-01 00:00:00