| Gefitinib, a synthetic anilinoquinazoline, directly and specificly inhibits tyrosine kinase (TK) phosphorylation on the epidermal growth factor receptor (EGFR) by competing for the ATP-binding site, which leads to suppression of the EGFR pathway (HER-kinase axis).[1] Gefitinib has an IC50 of 1.2-3.7 μM and 0.04-0.079 μM for HER2 and EGFR, respectively. EGFR mediates proliferation and survival mainly through phosphatidylinositol 3-kinase (PI3K)/Akt and Ras/Raf/mitogen-activated protein kinase (MAPK), the two main EGFR-signaling pathways. By colony formation assay, IC50 values of gefitinib (solubilized in DMSO) for the 8 non-small cell lung cancer (NSCLC) cell lines, PC9, A549, H522, H322, H358, H157, QG56, and LK2, are 0.06, 13, 13, 6.8, 2.0, 12, 7. and 8.0 μM, respectively and IC50 values of gefitinib for the two epidermoid cancer cell lines, KB3-1 and A431, are 10 μM and 0.4 μM, respectively. Gefitinib inhibits phosphorylation of EGFR, protein kinase B/AKT, and extracellular signal-regulated kinase (ERK) 1/2 in three of the NSCLC cell lines (PC9, A549, and QG56) in dose-dependent manner (0.1, 0.5, 1 and 5 μM).[2] In human breast cancer cell lines, the mean 50%-growth inhibitory concentrations of gefitinib are 28.5 μM for KPL-1 cells, 25.0 μM for KPL-3C cells, 25.0 μM for T47 D cells, 10.0 μM for KPL-4 cells and 10.0 μM for MDA-MB-231 cells, respectively. Besides, 10 μM gefitinib alone significantly increases the sub-G1 fraction in MDA-MB-231 cells. [3] Gefitinib-Resistant (GR) in vivo model can be generated as follows: Female mice are injected with minced CWR22R tumor and treated 5 days/week oral gavage with 100 mg/kg gefitinib for 3 weeks before the tumors are removed and passaged to new female mice. Tumor passaging is continued for a total of 12 generations until a GR line is generated. For xenograft experiments, gefitinib treatment of athymic nude mice bearing subcutaneous androgen-independent (CWR22R) xenograft tumors results in significant reduction in tumor growth (63% growth inhibition).[4] In athymic nude mice bearing A431 (vulval squamous carcinoma), A549 lung and Du145 prostate tumor xenografts, p.o. treatment once a day with gefitinib inhibits tumor growth in a dose-dependent manner. The AED50 is about 50 mg/kg, and the highest dose, 200 mg/kg gefitinib, prevents tumor growth. Furthermore, in mice bearing A431 xenografts, long-term treatment with gefitinib for more than 3 months beginning 7 days after tumor implantation completely blocks tumor growth. [1] |
