Linked Life Data

12183653

Source:http://linkedlifedata.com/resource/pubmed/id/12183653

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2002-8-16
pubmed:abstractText
Selective inhibition of the multidrug resistance 1 (MDR1) gene and its product, the P-glycoprotein, a membrane transporter responsible for multidrug resistance, could be an important approach for enhancing cancer therapeutics. An emerging strategy for selective gene regulation involves designed zinc finger proteins that can recognize specific sequences in the promoter regions of disease-related genes. Herein, we investigate the behavior of clones of multidrug-resistant NCI/ADR-RES breast carcinoma cells displaying ponasterone-inducible expression of a designed transcriptional repressor targeted to the MDR1 promoter. The controlled production of this novel repressor resulted in major reductions in P-glycoprotein levels in these otherwise highly drug-resistant tumor cells. The regulated reduction of MDR1 expression in NCI/ADR-RES cells was accompanied by a marked increase in the rate of uptake of the P-glycoprotein substrate rhodamine 123. In addition, the cytotoxicity profile of the antitumor drug doxorubicin was dramatically altered in the induced cells compared with controls. The expression levels of other genes were examined both by a DNA array analysis of approximately 2000 genes and by biochemical techniques. Although some changes were observed in mRNA levels of nontargeted genes, the most dramatic effect by far was on MDR1, indicating that the action of the designed transcriptional repressor was quite selective. This study suggests that designed transcriptional regulators can be used to strongly and selectively influence expression of cancer-related genes, even under circumstances of extensive amplification of the target gene.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
302
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
963-71
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12183653-Antibiotics, Antineoplastic, pubmed-meshheading:12183653-Antineoplastic Agents, pubmed-meshheading:12183653-Blotting, Northern, pubmed-meshheading:12183653-Blotting, Western, pubmed-meshheading:12183653-Doxorubicin, pubmed-meshheading:12183653-Flow Cytometry, pubmed-meshheading:12183653-Fluorescent Dyes, pubmed-meshheading:12183653-Gene Expression Regulation, Neoplastic, pubmed-meshheading:12183653-Genes, MDR, pubmed-meshheading:12183653-Humans, pubmed-meshheading:12183653-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:12183653-P-Glycoproteins, pubmed-meshheading:12183653-Plasmids, pubmed-meshheading:12183653-RNA, Neoplasm, pubmed-meshheading:12183653-Repressor Proteins, pubmed-meshheading:12183653-Rhodamine 123, pubmed-meshheading:12183653-Transfection, pubmed-meshheading:12183653-Tumor Cells, Cultured
pubmed:year
2002
pubmed:articleTitle
Selective inhibition of P-glycoprotein expression in multidrug-resistant tumor cells by a designed transcriptional regulator.
pubmed:affiliation
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 29799, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.