生物活性

• 描述EGFR (epidermal growth factor receptor) family consists of four members that belong to the ErbB lineage of proteins (ErbB1 - 4) with an external domain that binds activating ligands, such as EGF, and is overexpressed in a significant percentage of carcinomas and contributes to the malignant phenotype. Upon activation, EGFR phosphorylates both the receptor itself and a variety of “effector” protein. Gefitinib is an effective EGFR inhibitor with IC50 values of 37 nM, 37 nM, 26 nM and 57 nM for Tyr1173, Tyr992, Tyr1173 and Tyr992 EGFR sites (measured by EGFR tyrosine phosphorylations in cells), respectively in NR6 wt EGFR and NR6W cells. Gefitinib can sufficiently suppress all tyrosine phosphorylation sites, with less sensitivity to Tyr1173 and Tyr992 sites, on EGFR in both the high and low-EGFR-expressing cell lines, as well as EGFR-mediated proliferation. However, EGFR-mediated anchorage-independent growth was not sufficient to inhibit these features in cells expressing EGFRvIII, with approximately four times as resistant to gefitinib as EGFR. Long-term exposure of EGFRvIII-expressing cells to low concentrations of gefitinib (0.01 - 0.1 μM) resulted in increased phosphotyrosine load of the receptor, increased signaling to ERK and stimulation of proliferation and anchorage-independent growth while higher concentrations of gefitinib (1 - 2 μM) completely showed the opposite effect, presumably by inducing EGFRvIII dimerization^[1]. Gefitinib (40 mg/kg body weight/day) showed significant inhibition of tumor load when treated with weekly or weekly intermittent dosing regimens in lung adenocarcinoma model whereas a daily dosing regimen did not decrease the tumor load significantly^[2].
• 作用机制Gefitinib is an ATP-competitive inhibitor of EGFR^[3].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  16HBE	-	Growth Inhibition Assay	72 h	Antiproliferative activity against human 16HBE cells expressing wild type EGFR with IC50 of 1.601 μM	23792318
  16HBE	100 μM	Function Assay	150 min	Induction of nitric oxide production in human 16HBE cells expressing wild type EGFR	23792318
  16HBE14o-	10 μM	Cytotoxic Assay	72 h	Cytotoxicity against human 16HBE14o- cells harboring wild type EGFR assessed as growth inhibition with IC50 of 12.71 μM	23668441

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• 动物研究
  剂量	Mice (p.o.): min = 5 mg/kg[4], max = 300 mg/kg[5]
  给药途径	p.o.
  动物药代数据	Animal Rats[6] Dose 5 mg/kg Administration i.v. p.o. Cmax 230 ng/ml (p.o.) T1/2 5.3 h (i.v.) 4.1 h (p.o.) Vdss 9.8 L/kg (i.v.) AUC0-8 1130 ng·h/ml (p.o.) F 49.8% (p.o.) AUC0-inf 3540 ng·h/ml (i.v.) 1780 ng·h/ml (p.o.) Tmax 4 h (p.o.) CL 23.6 ml/min/kg (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00206414	BREAST CANCER	Phase 2	Terminated(Difficulty accruing... more >> subjects the study accrual was closed) Collapse <<	-	United States, Texas ... more >> Baylor Breast Center Houston, Texas, United States, 77030 Collapse <<
  NCT00820417	Colorectal Cancer ... more >> Head and Neck Cancer Non Small Cell Lung Cancer (NSCLC) Collapse <<	Phase 1	Completed	-	Belgium ... more >> UZ Gasthuisberg Leuven, Belgium, 3000 Spain Hospital Universitari Vall d'Hebron Barcelona, Spain, 08035 Collapse <<
  NCT00025207	Advanced Malignant Mesotheliom... more >>a Epithelial Mesothelioma Recurrent Malignant Mesothelioma Sarcomatous Mesothelioma Collapse <<	Phase 2	Completed	-	United States, Illinois ... more >> Cancer and Leukemia Group B Chicago, Illinois, United States, 60606 Collapse <<

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• 参考文献

• [1] Pedersen MW, Pedersen N, et al. Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII. Br J Cancer. 2005 Oct 17;93(8):915-23.

  [2] Zhang Q, Li R, et al. Effect of weekly or daily dosing regimen of Gefitinib in mouse models of lung cancer. Oncotarget. 2017 Aug 2;8(42):72447-72456.

  [3] Gokhale AG, Rajagopal P, et al. Cockroach in right main bronchus--an unusual foreign body. Indian J Chest Dis Allied Sci. 1992 Apr-Jun;34(2):103-5.

  [4] Kishino D, Kiura K, et al. Effect of gefitinib on N-nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced lung tumorigenesis in A/J mice. Lung Cancer. 2009 Sep;65(3):284-9.

  [5] Mikumo H, Yanagihara T, et al. Neutrophil elastase inhibitor sivelestat ameliorates gefitinib-naphthalene-induced acute pneumonitis in mice. Biochem Biophys Res Commun. 2017 Apr 22;486(1):205-209.

  [6] Pharmacokinetics of gefitinib

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