Gefitinib

Gefitinib, also known as ZD1839 or Iressa, is a potent and orally-bioavailable small-molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase with 50% inhibition concentration IC₅₀ values of 0.033 μM and 0.027 μM in A431 membrane prep and baculovirus lysate respectively. Gefitinib binds to the kinase ATP binding site of EGFR interfering with the binding of adenosine triphosphate, which suppresses the EGFR tyrosine kinase activity and resultant signal transduction of EGFR. Gefitinib exhibits anti-angiogenic activities in a wide range of human tumor types, including head and neck, prostate, breast, ovarian, colon, small-cell lung and non-small-cell lung cancer. Moreover, geftinib has also been found to reduce proliferation, induce cell cycle arrest and increase apoptosis.

Reference

M. Ranson and S. Wardell. Gefitinib, a novel, orally administered agent for the treatment of cancer. Journal of Clinical Pharmacy and Therapeutics (2004) 29, 95-103

Joachim Von Pawel. Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors. Bull Cancer 2004; 91(5): E70-E76

Effect of gefitinib plus Chinese herbal medicine (CHM) in patients with advanced non-small-cell lung cancer: a retrospective case-control study.[Pubmed:25453521]

Complement Ther Med. 2014 Dec;22(6):1010-8.

BACKGROUND: Some patients with non-small-cell lung cancer (NSCLC) respond well to the EGFR tyrosine kinase inhibitor Gefitinib. Chinese herbal medicine (CHM) was effective in improving the quality of life and prolonging overall survival in patient with NSCLC. We aim to determine whether Gefitinib plus CHM could prolong the progression-free survival (PFS) or median survival time (MST) in patients with NSCLC than Gefitinib alone. METHODS: We retrospectively analyzed 159 non-small-cell lung cancer patients with the method of retrospective case-control study, matching factors included gender, age categories (30-39,40-49,50-59,60-69,70-79), pathological stage (IIIB or IV), smoking status (never: <100 lifetime cigarettes, or ever: >/=100 lifetime cigarettes), pathology, and performance status. Among the 159 patients, 100 patients treated with Gefitinib (250mg/day orally) plus CHM ("Fuzheng Kang'ai" decoction, a Chinese herbal medicine, 250ml/bid/day orally), 59 patients treated with Gefitinib (250mg/day orally) only. PFS and MST were analyzed for the whole population. RESULTS: 58 pairs were matched successfully. 1 patient (treated with Gefitinib) with the age of 27 years failed to be matched. Progression-free survival was significantly longer in patients treated with Gefitinib plus CHM than with Gefitinib: median PFS was 13.1 months (95% CI 6.50-19.70) with Gefitinib plus CHM versus 11.43 months (95% CI 7.95-14.91) with Gefitinib (log-rank P=0.013). Median overall survival was longer with Gefitinib plus CHM than with Gefitinib: median MST was 22.83 months (95% CI 17.51-28.16) with Gefitinib plus CHM versus 18.7 months (95% CI 16.83-20.57) with Gefitinib (log-rank P=0.049). The most common adverse event was rash, the incidence in the Gefitinib plus CHM group was 41.38% while in the Gefitinib group was 24.14% (P=0.048). CONCLUSIONS: This case-control analysis suggested that treatment with Gefitinib plus CHM prolonged PFS and MST compared with Gefitinib in patients with NSCLC, and it is worthy of further study.

Gefitinib-mediated reactive oxygen specie (ROS) instigates mitochondrial dysfunction and drug resistance in lung cancer cells.[Pubmed:25681445]

J Biol Chem. 2015 Apr 3;290(14):9101-10.

Therapeutic benefits offered by tyrosine kinase inhibitors (TKIs), such as Gefitinib (Iressa) and erlotinib (Tarceva), are limited due to the development of resistance, which contributes to treatment failure and cancer-related mortality. The aim of this study was to elucidate mechanistic insight into cellular perturbations that accompany acquired Gefitinib resistance in lung cancer cells. Several lung adenocarcinoma (LAD) cell lines were screened to characterize epidermal growth factor receptor (EGFR) expression and mutation profile. To circumvent intrinsic variations between cell lines with respect to response to drug treatments, we generated Gefitinib-resistant H1650 clone by long-term, chronic culture under Gefitinib selection of parental cell line. Isogenic cells were analyzed by microarray, Western blot, flow cytometry, and confocal and transmission electron microscope. We observed that although chronic Gefitinib treatment provided effective action against its primary target (aberrant EGFR activity), secondary effects resulted in increased cellular reactive oxygen species (ROS). Gefitinib-mediated ROS correlated with epithelial-mesenchymal transition, as well as striking perturbation of mitochondrial morphology and function. However, Gefitinib treatment in the presence of ROS scavenger provided a partial rescue of mitochondrial aberrations. Furthermore, withdrawal of Gefitinib from previously resistant clones correlated with normalized expression of epithelial-mesenchymal transition genes. These findings demonstrate that chronic Gefitinib treatment promotes ROS and mitochondrial dysfunction in lung cancer cells. Antioxidants may alleviate ROS-mediated resistance.

Calcitriol and its analogues enhance the antiproliferative activity of gefitinib in breast cancer cells.[Pubmed:25510900]

J Steroid Biochem Mol Biol. 2015 Apr;148:122-31.

Coexpression of EGFR and HER2 has been associated with poor disease outcome, high rates of metastasis and resistance to conventional treatments in breast cancer. Gefitinib, a tyrosine kinase inhibitor, reduces both cell proliferation and tumor growth of breast cancer cells expressing EGFR and/or HER2. On the other hand, calcitriol and some of its synthetic analogs are important antineoplastic agents in different breast cancer subtypes. Herein, we evaluated the effects of the combined treatment of Gefitinib with calcitriol or its analogs on cell proliferation in breast cancer cells. The presence of EGFR, HER2 and vitamin D receptor were evaluated by Western blot in two established breast cancer cell lines: SUM-229PE, SKBR3 and a primary breast cancer-derived cell line. The antiproliferative effects of Gefitinib alone or in combination with calcitriol and its analogs, calcipotriol and EB1089, were assessed by growth assay using a DNA content-based method. Inhibitory concentrations on cell proliferation were calculated by non-linear regression analysis using sigmoidal fitting of dose-response curves. Pharmacological effects of the drug combinations were calculated by the Chou-Talalay method. Phosphorylation of ERK1/2 MAPK was evaluated by Western blot. Gene expression of EGFR, HER2 and BIM was assessed by real time PCR. BIM protein levels were analyzed in cells by flow cytometry. The effects of the drugs alone or combinated on cell cycle phases were determined using propidium iodide. Apoptosis was evaluated by detection of subG1 peak and determination of active caspase 3 by flow cytometry. Gefitinib, calcitriol, calcipotriol and EB1089 inhibited cell proliferation in a dose dependent manner. The combinations of Gefitinib with calcitriol or its analogs were more effective to inhibit cell growth than each compound alone in all breast cancer cells studied. The gene expression of EGFR and HER2 was downregulated and not affected, respectively, by the combined treatment. Furthermore, phosphorylation of ERK 1/2 was inhibited a greater extent in co-treated cells than in the cells treated with alone compounds. The combination of Gefitinib with calcitriol or their synthetic analogs induced apoptosis in SUM-229PE cells, this was shown by the significant upregulation of BIM protein levels, higher percentages of cells in subG1 peak and increase of caspase 3-positive cells. The combination of Gefitinib with calcitriol or their synthetic analogs resulted in a greater antiproliferative effect than with either of the agents alone in EGFR and HER2 positive breast cancer cells. The mechanistic explanation for these results includes downregulation of MAPK signaling pathway, decrease of cells in G2/M phase and induction of apoptosis mediated by upregulation of BIM and activation of caspase 3. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor.[Pubmed:15827338]

Mol Cancer Ther. 2005 Apr;4(4):641-9.

The relative distribution of Gefitinib-related material in nude mice bearing s.c. human tumor xenografts and in an orthotopic rat lung tumor model was investigated following oral administration (50 mg/kg) of [14C]-Gefitinib. Selected tissue samples were monitored for radioactivity by liquid scintillation counting, whereas plasma and tumor extracts were assayed for Gefitinib and its major metabolites (M523595 and M537194) by high-performance liquid chromatography with tandem mass spectrometric detection. Tissue distribution was also determined by whole body autoradiography. Gefitinib was extensively distributed into the tissues of tumor-bearing mice and unchanged Gefitinib was shown to account for most of the tumor radioactivity. Concentrations of Gefitinib in mouse s.c. tumor xenografts were similar to skin concentrations and substantially greater (up to 12-fold based on area under the concentration-time curve) than plasma. Concentrations of Gefitinib-related material in an orthotopic rat lung tumor were similar to those in healthy lung tissue and were much higher than corresponding blood levels. Following treatment of breast cancer patients with oral Gefitinib (Iressa) 250 mg/d for > or = 14 days, Gefitinib concentrations (mean, 7.5 microg/g, 16.7 micromol/L) in breast tumor tissue were 42 times higher than plasma, confirming the preferential distribution of Gefitinib from blood into tumor tissue in the clinical situation. These Gefitinib tumor concentrations are considerably higher than those reportedly required in vitro to achieve complete inhibition of epidermal growth factor receptor autophosphorylation in both epidermal growth factor receptor mutant (0.2 micromol/L) and wild-type cells (2 micromol/L).

ZD1839 ('Iressa') as an anticancer agent.[Pubmed:11129170]

Drugs. 2000;60 Suppl 1:33-40; discussion 41-2.

ZD1839 ('Iressa') is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor which blocks signal transduction pathways implicated in the proliferation and survival of cancer cells and other host-dependent processes promoting cancer growth. In preclinical studies, ZD1839 produced reversible growth inhibition and growth delay in a wide range of tumour cell lines and human tumour xenografts. Moreover, this activity was enhanced when ZD1839 was coadministered with cytotoxic agents. Preliminary results from phase I trials in patients with advanced disease and a wide variety of tumour types suggest that ZD1839 has an acceptable tolerability profile and promising clinical efficacy, particularly in non-small cell lung cancer (NSCLC). ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC. In addition, further trials are ongoing or planned in a number of other tumour types.

Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor.[Pubmed:10815932]

Clin Cancer Res. 2000 May;6(5):2053-63.

Transforming growth factor alpha (TGF-alpha) is an autocrine growth factor for human cancer. Overexpression of TGF-alpha and its specific receptor, the epidermal growth factor receptor (EGFR), is associated with aggressive disease and poor prognosis. The EGFR has been proposed as a target for anticancer therapy. Compounds that block ligand-induced EGFR activation have been developed. ZD-1839 (Iressa) is a p.o.-active, quinazoline derivative that selectively inhibits the EGFR tyrosine kinase and is under clinical development in cancer patients. The antiproliferative activity of ZD-1839 alone or in combination with cytotoxic drugs differing in mechanism(s) of action, such as cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, doxorubicin, etoposide, topotecan, and raltitrexed, was evaluated in human ovarian (OVCAR-3), breast (ZR-75-1, MCF-10A ras), and colon cancer (GEO) cells that coexpress EGFR and TGF-alpha. ZD-1839 inhibited colony formation in soft agar in a dose-dependent manner in all cancer cell lines. The antiproliferative effect was mainly cytostatic. However, treatment with higher doses resulted in a 2-4-fold increase in apoptosis. A dose-dependent supra-additive increase in growth inhibition was observed when cancer cells were treated with each cytotoxic drug and ZD-1839. The combined treatment markedly enhanced apoptotic cell death induced by single-agent treatment. ZD-1839 treatment of nude mice bearing established human GEO colon cancer xenografts revealed a reversible dose-dependent inhibition of tumor growth because GEO tumors resumed the growth rate of controls at the end of the treatment. In contrast, the combined treatment with a cytotoxic agent, such as topotecan, raltitrexed, or paclitaxel, and ZD-1839 produced tumor growth arrest in all mice. Tumors grew slowly for approximately 4-8 weeks after the end of treatment, when they finally resumed a growth rate similar to controls. GEO tumors reached a size not compatible with normal life in all control mice within 4-6 weeks and in all single agent-treated mice within 6-8 weeks after GEO cell injection. In contrast, 50% of mice treated with ZD-1839 plus topotecan, raltitrexed, or paclitaxel were still alive 10, 12, and 15 weeks after cancer cell injection, respectively. These results demonstrate the antitumor effect of this EGFR-selective tyrosine kinase inhibitor and provide a rationale for its clinical evaluation in combination with cytotoxic drugs.

Gefitinib (ZD1839) is a potent, selective and orally active EGFR tyrosine kinase inhibitor with an IC50 of 33 nM. Gefitinib selectively inhibits EGF-stimulated tumor cell growth (IC50 of 54 nM) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. Gefitinib also induces autophagy. Gefitinib has antitumour activity.

Gefitinib,184475-35-2,Gefitinib, ZD 1839,Natural Products,EGFR, buy Gefitinib , Gefitinib supplier , purchase Gefitinib , Gefitinib cost , Gefitinib manufacturer , order Gefitinib , high purity Gefitinib