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Early prediction of response to Vorinostat in an orthotopic rat glioma model
NMR in biomedicine, 2012-09, Vol.25 (9), p.1104-1111
Wei, Li
Hong, Samuel
Yoon, Younghyoun
Hwang, Scott N.
Park, Jaekeun C.
Zhang, Zhaobin
Olson, Jeffrey J.
Hu, Xiaoping P.
Shim, Hyunsuk
2012
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Wei, Li
Hong, Samuel
Yoon, Younghyoun
Hwang, Scott N.
Park, Jaekeun C.
Zhang, Zhaobin
Olson, Jeffrey J.
Hu, Xiaoping P.
Shim, Hyunsuk
Titel
Early prediction of response to Vorinostat in an orthotopic rat glioma model
Ist Teil von
NMR in biomedicine, 2012-09, Vol.25 (9), p.1104-1111
Ort / Verlag
Chichester, UK: John Wiley & Sons, Ltd
Erscheinungsjahr
2012
Quelle
Wiley Online Library All Journals
Beschreibungen/Notizen
Glioblastoma is the most common primary brain tumor and is uniformly fatal despite aggressive surgical and adjuvant therapy. As 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 the 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) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. A major shortcoming of the use of HDAC inhibitors in the treatment of patients with brain tumors is the lack of reliable biomarkers to predict and determine response. Histological evaluation may reflect tumor viability following treatment, but is an invasive procedure and impractical for glioblastoma. 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, N‐acetylaspartate and creatine levels, typical changes reported in glioblastoma relative to normal brain tissues. The 1H MRS‐detectable metabolites of SAHA‐treated tumors were restored to those of normal‐like brain tissues. In addition, reduced inositol and N‐acetylaspartate 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. Copyright © 2012 John Wiley & Sons, Ltd. During carcinogenesis, tumor suppressor genes can be silenced by aberrant histone deacetylation caused by histone deacetylase (HDAC). A major shortcoming of the use of HDAC inhibitors in the treatment of patients with brain tumors is the lack of reliable prognostic biomarkers. The current work describes a preclinical study for the development of MRS‐based and histopathologic biomarkers, which correlate with the normalization of brain metabolism and function, and thus predict the therapeutic response to Vorinostat.
Sprache
Englisch
Identifikatoren
ISSN: 0952-3480
eISSN: 1099-1492
DOI: 10.1002/nbm.2776
Titel-ID: cdi_proquest_miscellaneous_1492613846
Format
–
Schlagworte
Adjuvants
,
Affect - drug effects
,
Animals
,
Behavior, Animal - drug effects
,
Brain - drug effects
,
Brain - metabolism
,
Brain - pathology
,
Brain Neoplasms - drug therapy
,
Brain Neoplasms - enzymology
,
Brain Neoplasms - genetics
,
Brain Neoplasms - metabolism
,
Cell Line, Tumor
,
depression
,
Disease Models, Animal
,
Gene Expression Regulation, Neoplastic - drug effects
,
glioma
,
Glioma - drug therapy
,
Glioma - enzymology
,
Glioma - genetics
,
Glioma - metabolism
,
histone deacetylase inhibitor
,
Histone Deacetylase Inhibitors - pharmacology
,
Histone Deacetylase Inhibitors - therapeutic use
,
Hydroxamic Acids - pharmacology
,
Hydroxamic Acids - therapeutic use
,
Intramolecular Lyases - genetics
,
Intramolecular Lyases - metabolism
,
Magnetic Resonance Imaging
,
Male
,
Metabolome - drug effects
,
MRS
,
myo-inositol
,
orthotopic
,
Prognosis
,
Rats
,
Rats, Inbred F344
,
RNA, Messenger - genetics
,
RNA, Messenger - metabolism
,
SAHA
,
Treatment Outcome
,
Vorinostat
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