Linked Life Data

12606787

Source:http://linkedlifedata.com/resource/pubmed/id/12606787

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2003-2-27
pubmed:abstractText
A candidate antitumor agent, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203), was empirically discovered through the National Cancer Institute's Anticancer Drug Screen from a unique growth inhibitory-response profile, indicating a novel mechanism of action. 5F-203 activates the CYP1 family of cytochrome P450, involving aryl hydrocarbon receptor translocation into the nucleus. To characterize more completely the pathways involved in 5F-203 toxicity, cDNA microarrays were used to determine gene expression changes in MCF-7, a 5F-203-sensitive breast cancer cell line, after treatment with 1 microM 5F-203. The mRNA expression of CYP1A1 and CYP1B1 were both increased approximately 20-fold after 24 h, but less after 6 h of treatment, confirming previous results. However, the most pronounced drug-induced change was in the PLAB gene, encoding one of the bone morphogenic proteins in the transforming growth factor-beta (TGF-beta) superfamily. Other induced gene expressions included the apoptosis-initiating receptor TNFRSF6 (CD95/FAS), the DNA-damage response genes CDKN1A (p21/Cip1), p53-induced gene-3, and DNA binding protein 2. In contrast, the transcription factor c-Myc showed reduced expression. Western blot analysis also showed induction of p53 protein expression in response to 5F-203 treatment. In contrast to the MCF-7 data, MDA-MB-435, a cancer cell line resistant to 5F-203, showed no change in expression of any of these genes or the p53 protein under the same conditions of 5F-203 treatment. These data are consistent with the idea that CYP1A1 and CYP1B1 activation leads to 5F-203 toxicity through DNA damage-induced apoptosis, as well as signaling through a variant member of the TGF-beta superfamily.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
63
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
766-72
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Genotoxic profiling of MCF-7 breast cancer cell line elucidates gene expression modifications underlying toxicity of the anticancer drug 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole.
pubmed:affiliation
SAIC-Frederick Inc., Screening Technologies Branch, Laboratory of Functional Genomics, National Cancer Institute--Frederick, National Institutes of Health, Frederick, Maryland, USA. monks@dtpax2.ncifcrf.gov
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.