PMID- 12467226
OWN - NLM
STAT- MEDLINE
DCOM- 20030127
LR  - 20200930
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 1
IP  - 2
DP  - 2001 Dec
TI  - The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 
      tyrosine kinase inhibitor, GW2016, on the growth of human normal and 
      tumor-derived cell lines in vitro and in vivo.
PG  - 85-94
AB  - The epidermal growth factor receptor (EGFR) and ErbB-2 transmembrane tyrosine 
      kinases are currently being targeted by various mechanisms in the treatment of 
      cancer. GW2016 is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase 
      domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM, 
      respectively. This report describes the efficacy in cell growth assays of GW2016 
      on human tumor cell lines overexpressing either EGFR or ErbB-2: HN5 (head and 
      neck), A-431 (vulva), BT474 (breast), CaLu-3 (lung), and N87 (gastric). Normal 
      human foreskin fibroblasts, nontumorigenic epithelial cells (HB4a), and 
      nonoverexpressing tumor cells (MCF-7 and T47D) were tested as negative controls. 
      After 3 days of compound exposure, average IC50 values for growth inhibition in 
      the EGFR- and ErbB-2-overexpressing tumor cell lines were < 0.16 microM. The 
      average selectivity for the tumor cells versus the human foreskin fibroblast cell 
      line was 100-fold. Inhibition of EGFR and ErbB-2 receptor autophosphorylation and 
      phosphorylation of the downstream modulator, AKT, was verified by Western blot 
      analysis in the BT474 and HN5 cell lines. As a measure of cytotoxicity versus 
      growth arrest, the HN5 and BT474 cells were assessed in an outgrowth assay after 
      a transient exposure to GW2016. The cells were treated for 3 days in five 
      concentrations of GW2016, and cell growth was monitored for an additional 12 days 
      after removal of the compound. In each of these tumor cell lines, concentrations 
      of GW2016 were reached where outgrowth did not occur. Furthermore, growth arrest 
      and cell death were observed in parallel experiments, as determined by 
      bromodeoxyuridine incorporation and propidium iodide staining. GW2016 treatment 
      inhibited tumor xenograft growth of the HN5 and BT474 cells in a dose-responsive 
      manner at 30 and 100 mg/kg orally, twice daily, with complete inhibition of tumor 
      growth at the higher dose. Together, these results indicate that GW2016 achieves 
      excellent potency on tumor cells with selectivity for tumor versus normal cells 
      and suggest that GW2016 has value as a therapy for patients with tumors 
      overexpressing either EGFR or ErbB-2.
FAU - Rusnak, D W
AU  - Rusnak DW
AD  - Department of Cancer Biology, GlaxoSmithKline, 5 Moore Drive, Research Triangle 
      Park, NC 27709, USA.
FAU - Lackey, K
AU  - Lackey K
FAU - Affleck, K
AU  - Affleck K
FAU - Wood, E R
AU  - Wood ER
FAU - Alligood, K J
AU  - Alligood KJ
FAU - Rhodes, N
AU  - Rhodes N
FAU - Keith, B R
AU  - Keith BR
FAU - Murray, D M
AU  - Murray DM
FAU - Knight, W B
AU  - Knight WB
FAU - Mullin, R J
AU  - Mullin RJ
FAU - Gilmer, T M
AU  - Gilmer TM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Furans)
RN  - 0 
      (N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl-6-(5-((methylsulfonyl)ethyl)aminomethyl)-2-furyl)-4-quinazolinamine)
RN  - 0 (Quinazolines)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
CIN - Mol Cancer Ther. 2011 Nov;10(11):2019. PMID: 22072804
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis
MH  - Blotting, Western
MH  - Cell Cycle/drug effects
MH  - Cell Division/*drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Epidermal Growth Factor/pharmacology
MH  - ErbB Receptors/*antagonists & inhibitors/metabolism
MH  - Female
MH  - Fibroblasts/drug effects
MH  - Furans/*pharmacology
MH  - Humans
MH  - Infant, Newborn
MH  - Mice
MH  - Mice, Nude
MH  - Mice, SCID
MH  - Neoplasms, Experimental/*drug therapy/metabolism/pathology
MH  - Phosphorylation
MH  - Precipitin Tests
MH  - Quinazolines/*pharmacology
MH  - Receptor, ErbB-2/*antagonists & inhibitors/metabolism
MH  - Signal Transduction/drug effects
MH  - Skin/cytology
MH  - Tumor Cells, Cultured/drug effects/metabolism
MH  - Xenograft Model Antitumor Assays
EDAT- 2002/12/07 04:00
MHDA- 2003/01/28 04:00
CRDT- 2002/12/07 04:00
PHST- 2002/12/07 04:00 [pubmed]
PHST- 2003/01/28 04:00 [medline]
PHST- 2002/12/07 04:00 [entrez]
PST - ppublish
SO  - Mol Cancer Ther. 2001 Dec;1(2):85-94.