Gefitinib (ZD1839)

 

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Biological Activity

Description	Gefitinib (ZD-1839) is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively.
Targets	Tyr1173 (NR6wtEGFR cells)	Tyr992 (NR6wtEGFR cells)	Tyr1173 (NR6W cells)	Tyr992 (NR6W cells)
IC50	37 nM	37nM	26 nM	57 nM [1]
In vitro	Gefitinib effectively inhibits all tyrosine phosphorylation sites on EGFR in both the high and low-EGFR-expressing cell lines including NR6, NR6M and NR6W cell lines. The phosphorylation sites Tyr1173 and Tyr992 are less sensitive requiring higher concentrations of Gefitinib for inhibition. Gefitinib effectively blocks the phosphorylation of PLC-γ, with IC50 of 27nM, in NR6W cells. The NR6wtEGFR and NR6M cell lines has low levels of PLC-γ phosphorylation but the level in the NR6M cell line is more resistant to inhibition by Gefitinib with IC50 of 43 nM and 369 nM, respectively. Gefitinib inhibits Akt phosphorylations, with IC50 of 220 and 263nM, in the low-EGFR- and -EGFRvIII-expressing cell lines, respectively. Gefitinib in the dose range from 0.1 to 0.5μM significantly facilitates, rather than abrogates, colony formation of NR6M cells. However, at a concentration of 2 μM Gefitinib completely blocks NR6M colony formation. Gefitinib rapidly and in a dose-dependent manner inhibits EGFR and ERK phosphorylation up to 72 hours after EGF stimulation in both the high- and low-EGFR-expressing cell lines. [1] Gefitinib is the monolayer growth of these EGF-driven untransformed MCF10A cells with an IC50 of 20 nM. [2] The combination of Gefitinib (0.2 μM and 0.5 μM) with irradiation lead to a significant growth inhibition in LoVo cells, compared with radiation alone.. [3]
In vivo	Gefitinib (100 mg/kg) improves the anti-tumor effect of radiotherapy in LoVo tumor xenografts. [3] Gefitinib treatment of nude mice bearing established human GEO colon cancer xenografts reveals a reversible dose-dependent inhibition of tumor growth because GEO tumors resumes the growth rate of controls at the end of the treatment. [4]
Features	A potent EGFR tyrosine kinase inhibitor.

Protocol(Only for Reference)

Cell Assay: ^[1]

Cell lines	NR6, NR6M and NR6W cells
Concentrations	0-2 μM
Incubation Time	72 hours
Method	Exponentially growing cells including NR6, NR6M, NR6M and NR6W cells are seeded in sextuple in 96-well plates at a concentration of 2000 cells/well, allowed to adhere and subsequently washed in PBS and incubated overnight in medium containing 0.5% FCS. Cells are then treated with varying concentrations (0-2 μM) of Gefitinib or the solute control DMSO and EGF. The optimal EGF concentration for inducing proliferation of NR6wtEGFR and NR6W cells has previously been determined and hence NR6wtEGFR and NR6W cells are supplemented with 10 nM and 0.1 nM EGF, respectively. EGF is not added to NR6 and NR6M cells. After 72 hours the amount of cells are measured by performing a MTT proliferation assay.

Animal Study: ^[3]

Animal Models	Female nude mice (cba nu/nu) aged 8–10 weeks are intra-dermal injected with LoVo cells.
Dosages	100 mg/kg
Administration	Once daily by oral administration (0.1 mL/10 g body weight) for 14 days
Solubility	0.5% methylcellulose/0.2% Tween 80, 12 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01933347	Not yet recruiting	Non Small Cell Lung Cancer	Guangdong Association of Clinical Trials	2013-10	Phase 2
NCT01965275	Not yet recruiting	Self Efficacy|Drug Toxicity	Anhui Medical University	2013-10	Phase 2
NCT01963195	Not yet recruiting	NSCLC	Anhui Medical University	2013-10	Phase 2
NCT01982955	Not yet recruiting	Non-small Cell Lung Cancer	Merck KGaA	2013-12	Phase 1|Phase 2
NCT02013089	Recruiting	Gastrointestinal Cancers	Sun Yat-sen University	2013-12

Chemical Information

Download Gefitinib (ZD1839) SDF

Chemical Name	N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.4469	4.469	8.938	13.407

Customer Reviews (11)

Click to enlarge	Rating
	Source	Mol Biosyst, 2011, 7(12), 3223-33. Gefitinib (ZD1839) purchased from Selleck
	Method	Immunoprecipitation/Western blotting
	Cell Lines
	Concentrations	5 μM
	Incubation Time	0-1 h
	Results	In the presence of the EGFR tyrosine kinase inhibitor Z D1839 (Iressa) revealed that the observed increase in binding between PCM1 and Azi1 is specific to EGFs timulation and requires E GFR activation.

Product Citations (39)

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  Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. [Prahallad A, et al. Nature 2012;483(7387):100-3]

  
  PubMed: 22281684


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  MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. [Huang S, et al. Cell 2012;151(5):937-50]

  
  PubMed: 23178117


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  Network modeling of the transcriptional effects of copy number aberrations in glioblastoma. [Jornsten R, et al. Mol Syst Biol 2011;7:486]

  
  PubMed: 21525872