Linked Life Data

12939459

Source:http://linkedlifedata.com/resource/pubmed/id/12939459

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2003-8-26
pubmed:abstractText
Gastrointestinal stromal tumors (GISTs), defined by the presence of constitutively activated KIT, are the most common gastrointestinal mesenchymal malignancies. This observation has been successfully exploited in clinical trials of Gleevec (also known as imatinib mesylate, STI-571) for patients with unresectable and/or metastatic GISTs. The biological mechanisms of Gleevec as well as its downstream molecular effects are generally unknown. We used a DNA microarray-based approach to identify gene expression patterns and signaling pathways that were altered in response to Gleevec in GIST cells. We identified a total of 148 genes or expressed sequence tags (of 10,367) that were differentially regulated; 7 known genes displayed a durable response after treatment. The significantly down-regulated genes were SPRY4A, FZD8, PDE2A, RTP801, FLJ20898, and ARHGEF2. The only up-regulated gene was MAFbx. On a functional level, we demonstrated that imatinib inhibited phosphorylation of KIT, AKT, and extracellular signal-regulated kinase 1/2 without affecting the total level of these proteins and that differential expression of these response genes involved activation of mitogen-activated protein kinase-dependent and -independent pathways. In an attempt to correlate these in vitro findings to clinical data, we examined GIST needle biopsy specimens taken from patients before and after Gleevec administration according to the CSTI571-B2222 Phase II trial and demonstrated that expression levels of the two gene transcripts evaluated correlated well with clinical response. This study emphasizes the potential value of an in vitro cell model to investigate GIST response to imatinib in vivo, for the purpose of identifying important genetic markers of clinical response, mechanisms of drug action, and possible therapeutic targets.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1535-7163
pubmed:author
pubmed:issnType
Print
pubmed:volume
2
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
699-709
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12939459-Antineoplastic Agents, pubmed-meshheading:12939459-Biopsy, Needle, pubmed-meshheading:12939459-Cell Line, pubmed-meshheading:12939459-Down-Regulation, pubmed-meshheading:12939459-Gastrointestinal Neoplasms, pubmed-meshheading:12939459-Gene Expression Regulation, pubmed-meshheading:12939459-Gene Targeting, pubmed-meshheading:12939459-Genetic Markers, pubmed-meshheading:12939459-Muscle Proteins, pubmed-meshheading:12939459-Neoplasm Proteins, pubmed-meshheading:12939459-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:12939459-Phosphorylation, pubmed-meshheading:12939459-Piperazines, pubmed-meshheading:12939459-Proto-Oncogene Proteins c-kit, pubmed-meshheading:12939459-Pyrimidines, pubmed-meshheading:12939459-SKP Cullin F-Box Protein Ligases, pubmed-meshheading:12939459-Signal Transduction, pubmed-meshheading:12939459-Stromal Cells
pubmed:year
2003
pubmed:articleTitle
Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors.
pubmed:affiliation
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't