Source:http://linkedlifedata.com/resource/pubmed/id/11259619
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
4
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| pubmed:dateCreated |
2001-3-22
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| pubmed:abstractText |
Transcriptional silencing of tumor suppressor genes by DNA methylation occurs in cancer cell lines and in human tumors. This has led to the pursuit of DNA methyltransferase inhibition as a drug target. 5-Aza-2'-deoxycytidine [5-aza-CdR (decitabine)], a potent inhibitor of DNA methyltransferase, is a drug currently in clinical trials for the treatment of solid tumors and leukemia. The efficacy of 5-aza-CdR may be related to the induction of methylation-silenced tumor suppressor genes, genomic hypomethylation, and/or enzyme-DNA adduct formation. Here, we test the hypothesis that 5-aza-CdR treatment is perceived as DNA damage, as assessed by the activation of the tumor suppressor p53. We show that 1) colon tumor cell lines expressing wild-type p53 are more sensitive to 5-aza-CdR mediated growth arrest and cytotoxicity; 2) the response to 5-aza-CdR treatment includes the induction and activation of wild-type but not mutant p53 protein; and 3) the induction of the downstream p53 target gene p21 is partially p53-dependent. The induction of p53 protein after 5-aza-CdR treatment did not correlate with an increase in p53 transcripts, indicating that hypomethylation at the p53 promoter does not account for the p53 response. It is relevant that 5-aza-CdR has shown the greatest promise in clinical trials for the treatment of chronic myelogenous leukemia, a malignancy in which functional p53 is often retained. Our data raise the hypothesis that p53 activation may contribute to the clinical efficacy and/or toxicity of 5-aza-CdR.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antimetabolites, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/Azacitidine,
http://linkedlifedata.com/resource/pubmed/chemical/CDKN1A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Modification Methylases,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53,
http://linkedlifedata.com/resource/pubmed/chemical/decitabine
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| pubmed:status |
MEDLINE
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| pubmed:month |
Apr
|
| pubmed:issn |
0026-895X
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
59
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
751-7
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| pubmed:dateRevised |
2006-5-5
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| pubmed:meshHeading |
pubmed-meshheading:11259619-Antimetabolites, Antineoplastic,
pubmed-meshheading:11259619-Azacitidine,
pubmed-meshheading:11259619-Cell Survival,
pubmed-meshheading:11259619-Colonic Neoplasms,
pubmed-meshheading:11259619-Cyclin-Dependent Kinase Inhibitor p21,
pubmed-meshheading:11259619-Cyclins,
pubmed-meshheading:11259619-DNA Damage,
pubmed-meshheading:11259619-DNA Methylation,
pubmed-meshheading:11259619-DNA Modification Methylases,
pubmed-meshheading:11259619-Enzyme Inhibitors,
pubmed-meshheading:11259619-G1 Phase,
pubmed-meshheading:11259619-Gene Expression Regulation,
pubmed-meshheading:11259619-HT29 Cells,
pubmed-meshheading:11259619-Humans,
pubmed-meshheading:11259619-Mutation,
pubmed-meshheading:11259619-RNA, Messenger,
pubmed-meshheading:11259619-Tumor Cells, Cultured,
pubmed-meshheading:11259619-Tumor Suppressor Protein p53
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| pubmed:year |
2001
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| pubmed:articleTitle |
Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2'-deoxycytidine.
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| pubmed:affiliation |
Division of Molecular Pharmacology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
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| pubmed:publicationType |
Journal Article
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