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GEFITINIB; A POTENT INHIBITOR OF EGFR

by Selleckchem | Jul 11 2012

INTRODUCTION AND MECHANISM OF ACTION
There are many inhibitors of tyrosine kinase inhibitors and amongst these Gefitinib is one of the potent inhibitor. It gently inhibits the functions of EGFR or epidermal growth factor receptor. Currently there are two companies are producing Gefitinib including Astra Zeneca Company and Teva Company. Gefitinib Iressa performs its functions by inhibiting EGFR due to its structural properties which contains a ring structure of anilinoquinazoline. Gefitinib EGFR inhibitor costs around 80$ for a vial of 1g and it is available for anyone desired to purchase Gefitinib including researchers, scientists and for laboratory uses. Gefitinib is not soluble in water however Gefitinib solubility can be attained in ethanol, dimethyl sulfoxide (DMSO) and DMF. As far Gefitinib stability is concerned it is stable for a period of 2 years if stored at -20oC. Gefitinib IC50 is 37nM and 57nM for Tyr 1173 and Try 992 respectively. There were many assays were performed for the pharmacokinetics and sensitivity evaluation of Gefitinib. These assays were based on the information of some presumptive markers such as mutated forms of K-Ras and EGFR and variable copy number. Enzyme linked immunosorbent assay (ELISA) is carried out to analyze human serum [1] and study of tissues against a specific drugs or HDRA [2]. This is a competitor inhibitor of EGFR which competes with ATP and binds with ATP binding site present in EGFR which ultimately results in the inhibition of ligand binding and therefore inhibits the signal transduction which is caused by ligand binding.

VARIOUS STUDIES OF GEFITINIB
Gefitinib shows anti cancer properties when it is used alone or in combination with other therapeutics according to the studies done so far and this inhibitor is promising as well. During the studies of Gefitinib effects on human breast cancer cells when it was administered with Herceptin and the growth of cells was inhibited as these cancer monolayer cells express ErbB-2 and EGFR [3]. Different research reports revealed the similar effects. Gefitinib was also used for analyzing the effects of different levels of EGFR and having high level of ErbB-2 cells on the proliferation of cells [4]. This inhibitor proved as an effective drug against breast cancer cell lines having different levels of EGFR and HER-2, in these cells apoptosis was initiated by Gefitinib [5]. However apart from breast cancer treatment Gefitinib has also been used for upper aerodigestive tract cancer treatment [6].

CLINICAL TRIALS STUDIES OF GEFITINIB
Like many other therapeutic drugs for the evaluation of different properties of Gefitinib clinical trials were conducted. Gefitinib clinical trials in phase I included patients having metstatic solid tumors and Gefitinib was administered in order to analyze its tolerability, pharmacokinetic and anti-apoptotic properties [7]. During phase III of clinical trials patients of lung adenocarcinoma who were untreated previously were exposed to Gefitinib EGFR inhibitor and it was reported that this drug is more effective than Paclitaxel and Carboplatin, therefore it can be the first choice for the cancer treatment [8]. In case of metastatic brain tumor it also proved as efficient [9]. In clinical phase II patients of Glioblastoma multiform were treated with Gefitinib and the efficiency of this inhibitor was studied [10]. Due to the properties of Gefitinib it has also been used in patients with relapsed GBM during clinical phase II trials [11].
More recently neoadjuvants of Gefitinib was used in combination with other therapeutics against breast cancer having estrogen receptor [12]. It was also used for the treatment of hormonerefractory type prostate cancer [13]. The therapy of Nesothelioma (NCT00787410) was recommended in favor of Gefitinib as studied by Astra Zeneca in phase II of clinical trials.

GEFITINIB AND NSCLC
When NSCLC patients were treated with Gefitinib efficient results were noted [14]. For the therapy of NSCLC Gefitinib along with other drugs has been evaluated [15]. Patients having no smoking history when exposed to Gefitinib and Erlotinib showed promising results for the therapy of adenocarcinoma [16]. In clinical trials of phase III it was also used against NSCLS [17] and in these studies it was also noted that Gefitinib is more effective than Docetaxel against NSCLC [18].

REFERENCES:
1. TETSUYA, S.e.a., A Specific and Sensitive Assay for Gefitinib Using the Enzyme-Linked Immunosorbent Assay in Human Serum. Biol Pharm Bull, 2005.
2. Yoshimasu, T.e.a., Histoculture drug response assay for gefitinib in non-small-cell lung cancer. General Thoracic and Cardiovascular Surgery, 2007.
3. Normanno, N.e.a., Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol, 2002.
4. Anderson, N.G.e.a., ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression. Int J Cancer, 2001.
5. Anido, J.e.a., ZD1839, a Specific Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor, Induces the Formation of Inactive EGFR/HER2 and EGFR/HER3 Heterodimers and Prevents Heregulin Signaling in HER2-overexpressing Breast Cancer Cells. Clin Cancer Res, 2003.
6. Arteaga, C.L.a.J., D.H., Tyrosine kinase inhibitors-ZD1839 (Iressa). Curr Opin Oncol., 2001.
7. Ranson, M.e.a., ZD1839, a Selective Oral Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial Journal of Clinical Oncology, 2002.
8. Mok, T.S.e.a., Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med, 2009.
9. Cappuzzo, F.e.a., ZD 1839 in patients with brain metastases from non-small-cell lung cancer (NSCLC): report of four cases. British Journal of Cancer, 2003.
10. Hegi, M.E.e.a., Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib-A Phase II Trial Mol Cancer Ther, 2011.
11. Rich, J.N.e.a., Phase II Trial of Gefitinib in Recurrent Glioblastoma. Journal of Clinical Oncology, 2004.
12. Massarweh, S.e.a., A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer. Breast Cancer Research and Treatment, 2011.
13. Canil, C.M.e.a., Randomized Phase II Study of Two Doses of Gefitinib in Hormone-Refractory Prostate Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group. Journal of Clinical Oncology, 2005.
14. Sordella, R.e.a., Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science., 2004.
15. Han, J.Y.e.a., A Randomized Phase II Study of Gefitinib Plus Simvastatin Versus Gefitinib Alone in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer Clin Cancer Res, 2011.
16. Pao, W.e.a., EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A., 2004.
17. Fukuoka, M.e.a., Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non-Small-Cell Lung Cancer in Asia (IPASS). Journal of Clinical Oncology, 2011.
18. Kim, E.S.e.a., Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. The Lancet, 2008.

Cat.No.	Product Name	Information
S1025	Gefitinib	Gefitinib 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. Gefitinib promotes autophagy and apoptosis of lung cancer cells via blockade of the PI3K/AKT/mTOR pathway.
S1150	Paclitaxel	Paclitaxel is a microtubule polymer stabilizer with IC50 of 0.1 pM in human endothelial cells.Paclitaxel can cause both mitotic arrest and apoptotic cell death. Paclitaxel also induces autophagy.
S1215	Carboplatin	Carboplatin, a derivative of CDDP, is a DNA synthesis inhibitor which binds to DNA, inhibits replication and transcription and induces cell death and interfers with the cell's repair mechanism in A2780, SKOV-3, IGROV-1, and HX62 cells. It induces the formation of DNA interstrand crosslinks and DNA-protein crosslinks. Solutions are unstable and should be fresh-prepared.DMSO is not recommended to dissolve platinum-based drugs, which can easily lead to drug inactivation.