Linked Life Data

15382076

Source:http://linkedlifedata.com/resource/pubmed/id/15382076

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2004-9-21
pubmed:abstractText
The mechanism of action of ZR2002, a chimeric amino quinazoline designed to possess mixed EGFR tyrosine kinase (TK) inhibitory and DNA targeting properties, was compared to those of ZR01, a reversible inhibitor of the same class and PD168393, a known irreversible inhibitor of EGFR. ZR2002 exhibited 4-fold stronger EGFR TK inhibitory activity than its structural homologue ZR01 but was approximately 3-fold less active than the 6-acrylamidoquinazoline PD168393. It preferentially blocked EGF and TGFalpha-induced cell growth over PDGF and serum. It also inhibited signal transduction in heregulin-stimulated breast tumour cells, indicating that it does not only block EGFR but also its closely related erbB2 gene product. In contrast to its structural homologues, ZR2002 was capable of inducing significant levels of DNA strand breaks in MDA-MB-468 cells after a short 2 hr drug exposure at a concentration as low as 10 microM. Reversibility studies using whole cell autophosphorylation and growth assays in human breast cell lines showed that in contrast to its reversible inhibitor counterpart ZR01, ZR2002 induced irreversible inhibition of EGF-stimulated autophosphorylation in MDA-MB-468 cells and irreversible inhibition of cell growth. Moreover despite possessing a weaker binding affinity than PD168393, it induced a significantly more sustained antiproliferative effect than the latter after a pulse 2 hr exposure. More importantly, in contrast to ZR01 and PD168393, ZR2002 was capable of inducing significant levels of cell death by apoptosis in MDA-MB-468 cells. The results in toto suggest that the superior antiproliferative potency of ZR2002 may be due to its ability to induce a protracted blockade of receptor tyrosine kinase-mediated signaling while damaging cellular DNA, a combination of events that may trigger cell-killing by apoptosis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0020-7136
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
112
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
484-91
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15382076-Apoptosis, pubmed-meshheading:15382076-Breast Neoplasms, pubmed-meshheading:15382076-Cell Proliferation, pubmed-meshheading:15382076-DNA, Neoplasm, pubmed-meshheading:15382076-DNA Damage, pubmed-meshheading:15382076-Enzyme Inhibitors, pubmed-meshheading:15382076-Epidermal Growth Factor, pubmed-meshheading:15382076-Female, pubmed-meshheading:15382076-Humans, pubmed-meshheading:15382076-Molecular Structure, pubmed-meshheading:15382076-Oncogene Proteins v-erbB, pubmed-meshheading:15382076-Phosphorylation, pubmed-meshheading:15382076-Platelet-Derived Growth Factor, pubmed-meshheading:15382076-Quinazolines, pubmed-meshheading:15382076-Receptor, Epidermal Growth Factor, pubmed-meshheading:15382076-Signal Transduction, pubmed-meshheading:15382076-Transforming Growth Factor alpha, pubmed-meshheading:15382076-Tumor Cells, Cultured
pubmed:year
2004
pubmed:articleTitle
Multiple mechanisms of action of ZR2002 in human breast cancer cells: a novel combi-molecule designed to block signaling mediated by the ERB family of oncogenes and to damage genomic DNA.
pubmed:affiliation
Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, Montreal, Quebec, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't