Linked Life Data

16397255

Source:http://linkedlifedata.com/resource/pubmed/id/16397255

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2006-1-6
pubmed:abstractText
Coexpression of the epidermal growth factor receptor (EGFR) family receptors is found in a subset of colon cancers, which may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. Recently, efforts have been made to develop novel 4-anilinoquinazoline and pyridopyrimidine derivatives to inhibit EGFR and ErbB2 kinases simultaneously. In this study, we tested the efficacy of a novel reversible dual inhibitor GW572016 compared with the selective EGFR and ErbB2 tyrosine kinase inhibitors (TKI) AG1478 and AG879 and their combination, using the human colon adenocarcinoma GEO mode. GEO cells depend on multiple ErbB receptors for aberrant growth. A synergistic effect on inhibition of cell proliferation associated with induction of apoptosis was observed from the combination of AG1478 and AG879. Compared with AG1478 or AG879, the single TKI compound GW572016 was a more potent inhibitor of GEO cell proliferation and was able to induce apoptosis at lower concentrations. Western blot analysis revealed that AG1478 and AG879 were unable to suppress both EGFR and ErbB2 activation as well as the downstream mitogen-activated protein kinase (MAPK) and AKT pathways as single agents. In contrast, GW572016 suppressed the activation of EGFR, ErbB2, MAPK, and AKT in a concentration-dependent manner. Finally, in vivo studies showed that GW572016 treatment efficiently blocked GEO xenograft growth at a dose range of 30 to 200 mg/kg with a twice-daily schedule. In summary, our study indicates that targeting both EGFR and ErbB2 simultaneously could enhance therapy over that of single agents directed at EGFR or ErbB2 in cancers that can be identified as being primarily heterodimer-dependent.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
66
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
404-11
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16397255-Animals, pubmed-meshheading:16397255-Apoptosis, pubmed-meshheading:16397255-Cell Growth Processes, pubmed-meshheading:16397255-Cell Line, Tumor, pubmed-meshheading:16397255-Colonic Neoplasms, pubmed-meshheading:16397255-Drug Synergism, pubmed-meshheading:16397255-Humans, pubmed-meshheading:16397255-MAP Kinase Signaling System, pubmed-meshheading:16397255-Mice, pubmed-meshheading:16397255-Mice, Inbred BALB C, pubmed-meshheading:16397255-Mice, Nude, pubmed-meshheading:16397255-Phosphorylation, pubmed-meshheading:16397255-Protein Kinase Inhibitors, pubmed-meshheading:16397255-Proto-Oncogene Proteins c-akt, pubmed-meshheading:16397255-Quinazolines, pubmed-meshheading:16397255-Receptor, Epidermal Growth Factor, pubmed-meshheading:16397255-Receptor, erbB-2, pubmed-meshheading:16397255-Tyrphostins, pubmed-meshheading:16397255-Xenograft Model Antitumor Assays
pubmed:year
2006
pubmed:articleTitle
Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis.
pubmed:affiliation
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural