化合物信息

Description

Glioblastoma, Bladder cancer

Description

Gefitinib (Iressa, 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

IC₅₀

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] Gefitinib blocks EGF signalling in MDA-MB-231 cells. Gefitinib severely inhibits this increase in cell number in a dose-dependent manner. ^[3]

In Vivo

Gefitinib inhibits tumour growth of SKOV3 or MDA-MB-231 tumors in athymic nude mice. Gefitinib is effective against both types of tumour. Growth of MDA-MB-231 tumors over the 14-day treatment period is inhibited by approximately 71% and that of SKOV3 tumors by approximately 32%. ^[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]

Clinical Trials

Gefitinib has entered in a phase II clinical trial in the treatment of non small cell lung cancer.

Features

Gefitinib is a potent EGFR tyrosine kinase inhibitor.

Description

Coadministration of Gefitinib, as with anti-EGFR, will enhance the efficacy of cytotoxic agents against human vulvar (A431), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC-3 and TSU-PR1) tumors. Although Paclitaxel or Docetaxel, as single agents markedly inhibits the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3, when combined with Gefitinib, partial or complete regression is usually seen. Against A549, the growth inhibition of Doxorubicin is increased 10-fold (>99%) with Gefitinib. ^[5]

Cell Lines

NR6, NR6M and NR6W cells

Concentrations

0-2 μM

Incubation Time

72 hours

Methods

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 Models

Athymic nude mice bearing SKOV3 or MDA-MB-231 tumours

Formulation

0.2% DMSO

Doses

75 mg/kg

Administration

Gavage