Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Biom J ; 50(5): 801-23, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18932139

ABSTRACT

One of multiple testing problems in drug finding experiments is the comparison of several treatments with one control. In this paper we discuss a particular situation of such an experiment, i.e., a microarray setting, where the many-to-one comparisons need to be addressed for thousands of genes simultaneously. For a gene-specific analysis, Dunnett's single step procedure is considered within gene tests, while the FDR controlling procedures such as Significance Analysis of Microarrays (SAM) and Benjamini and Hochberg (BH) False Discovery Rate (FDR) adjustment are applied to control the error rate across genes. The method is applied to a microarray experiment with four treatment groups (three microarrays in each group) and 16,998 genes. Simulation studies are conducted to investigate the performance of the SAM method and the BH-FDR procedure with regard to controlling the FDR, and to investigate the effect of small-variance genes on the FDR in the SAM procedure.


Subject(s)
Biometry/methods , Oligonucleotide Array Sequence Analysis/statistics & numerical data , Drug Discovery/statistics & numerical data , Gene Expression Profiling/statistics & numerical data , Humans , Linear Models , Models, Statistical
2.
Br J Cancer ; 97(10): 1344-53, 2007 Nov 19.
Article in English | MEDLINE | ID: mdl-18000499

ABSTRACT

R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21waf1,cip1, a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Hydroxamic Acids/pharmacology , Neoplasms/drug therapy , Sulfones/pharmacology , Administration, Oral , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21/drug effects , Cyclin-Dependent Kinase Inhibitor p21/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Histones/drug effects , Histones/metabolism , Humans , Hydroxamic Acids/chemistry , Immunohistochemistry , Isoenzymes/antagonists & inhibitors , Male , Mice , Mice, Nude , Neoplasms/pathology , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/genetics , Rats , Rats, Sprague-Dawley , Sulfones/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...