Imperial College London
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ProfessorBobBrown

Faculty of Medicine, Department of Surgery & Cancer

Senior Research Investigator
 
 
 
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Contact

 

+44 (0)20 7594 1804b.brown Website

 
 
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Assistant

 

Ms Sophie Lions +44 (0)20 7594 2792

 
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Location

 

1 007Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Steele:2009:10.1038/sj.bjc.6604932,
author = {Steele, N and Finn, P and Brown, R and Plumb, JA},
doi = {10.1038/sj.bjc.6604932},
journal = {British Journal of Cancer},
pages = {758--763},
title = {Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo},
url = {http://dx.doi.org/10.1038/sj.bjc.6604932},
volume = {100},
year = {2009}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Histone deacetylation and DNA methylation have a central role in the control of gene expression in tumours, including transcriptional repression of tumour suppressor genes and genes involved in sensitivity to chemotherapy. Treatment of cisplatin-resistant cell lines with an inhibitor of DNA methyltransferases, 2-deoxy-5′azacytidine (decitabine), results in partial reversal of DNA methylation, re-expression of epigenetically silenced genes including hMLH1 and sensitisation to cisplatin both in vitro and in vivo. We have investigated whether the combination of decitabine and a clinically relevant inhibitor of histone deacetylase activity (belinostat, PXD101) can further increase the re-expression of genes epigenetically silenced by DNA methylation and enhance chemo-sensitisation in vivo at well-tolerated doses. The cisplatin-resistant human ovarian cell line A2780/cp70 has the hMLH1 gene methylated and is resistant to cisplatin both in vitro and when grown as a xenograft in mice. Treatment of A2780/cp70 with decitabine and belinostat results in a marked increase in expression of epigenetically silenced MLH1 and MAGE-A1 both in vitro and in vivo when compared with decitabine alone. The combination greatly enhanced the effects of decitabine alone on the cisplatin sensitivity of xenografts. As the dose of decitabine that can be given to patients and hence the maximum pharmacodynamic effect as a demethylating agent is limited by toxicity and eventual re-methylation of genes, we suggest that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumours that have acquired drug resistance due to DNA methylation and gene silencing.
AU  - Steele,N
AU  - Finn,P
AU  - Brown,R
AU  - Plumb,JA
DO  - 10.1038/sj.bjc.6604932
EP  - 763
PY  - 2009///
SN  - 0007-0920
SP  - 758
TI  - Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo
T2  - British Journal of Cancer
UR  - http://dx.doi.org/10.1038/sj.bjc.6604932
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000263905900013&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/57169
VL  - 100
ER  -
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