Imperial College London

DrNeloferSyed

Faculty of MedicineDepartment of Brain Sciences

Senior Research Fellow
 
 
 
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Contact

 

+44 (0)20 7594 5292n.syed

 
 
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Location

 

E506Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@inproceedings{Syed:2009,
author = {Syed, N},
title = {Deficiency of argininosuccinate synthetase expression confers sensitivity to arginine depletion with arginine deiminase in glioblastomas},
year = {2009}
}

RIS format (EndNote, RefMan)

TY  - CPAPER
AB - Despite aggressive radio-chemotherapy, the prognosis for patients with glioblastoma multiforme (GBM) remains poor. New agents are therefore required. The molecular mechanisms, which are key in the pathogenesis and progression of GBM are still poorly understood. A recent documented mutations of isocitrate dehydrogenase 1 and 2 in more than 70% of astrocytomas (Yah H, 2009) brought the attention on metabolism as a primary target in the development of novel treatment modalities for these tumours. Using de novo gene finding techniques and epigenetic profiling in human GBM cell lines and cultured explants of primary GBM, we observed frequent transcriptional silencing of the 2 most important enzymes of the arginine biosynthetic pathway: argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL). We observed that loss of expression of ASS1, as determined by RT-PCR and immunohistochemistry, confers arginine auxotrophy to GBM cell lines and primary tumour explants. This confers sensitivity to highly selective, dose-dependent killing of the cells by arginine deprivation due to either nutritional starvation or pharmacological depletion with pegylated arginine deiminase (ADI-PEG20, Polaris Pharmaceuticals, Inc., San Diego, CA, USA). We have further demonstrated on tumour tissue sections that 20% of de novo GBMs have little or no expression of ASS1 indicating that ASS1 expression tested by immunohistochemistry represents an excellent predictor of response to arginine deprivation with arginine deiminase treatment. These pharmacogenomic findings suggest that ASS1 negativity may serve as a biomarker to select a population sensitive to arginine depletion with ADI-PEG20. Further studies are warranted.
AU - Syed,N
PY - 2009///
TI - Deficiency of argininosuccinate synthetase expression confers sensitivity to arginine depletion with arginine deiminase in glioblastomas
ER -