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GEFITINIB – EGFR REGULATING DRUG FOR LUNG CANCER

GEFITINIB: PROPERTIES AND MECHANISM OF ACTION
There are two companies that are marketing Gefitinib named AstraZeneca and Teva. Gefitinib drug is actually Gefitinib EGFR inhibitor molecule that is an efficient and strong compound and has undergone clinical trials. Gefitinib structure reveals that a ring of anilinoquinazoline is present in it. Gefitinib price for a 1 gram vial is around $80 and due to its reasonable price one can purchase Gefitinib EGFR inhibitor very easily for laboratory or research purposes from any supplier Gefitinib. Gefitinib stability is for almost 2 years if stored at -20 degrees. To inhibit Tyr 1173 and Tyr 992 properly, the Gefitinib IC50 is found to be 57 nM and 37 nM respectively for inhibition of EGFR. Various Gefitinib assays were carried out to check the sensitivity and pharmacokinetic properties of this drug and those clinical assays were found to base upon some certain predictive markers like EGFR mutated genes, mutations in K-Ras and copy number. For routine purposes researchers prefers to perform ELISA enzyme linked immunosorbent assay) [2] or HDRA (histoculture drug response assay) [1] of human serum to analyze the pharmacokinetic properties of this drug. The mode of action behind the role of Gefitinib is to bind with EGFR ATP-binding region on surface of tumor cells competitively hence results in inhibition of ligand induced phosphorylation of EGFR tyrosine to analyze the down streaming pathways.


GEFITINIB: IN VITRO AND IN VIVO STUDIES 
The combined of Herceptin and Gefitinib were analyzed by applying them together on primary monolayers of human breast cancer expressing EGFR and ErbB-2 and the positive results for future were obtained [3]. These results were confirmed by the independent groups of researchers where the ability of Gefitinb to analyze the cell proliferation in high EGFR expression, low level EGFR expression and moderate levels of EGFR and high ErbB-2 expression was also checked [4]. The antiapoptotic properties of Gefitinb were also studied in breast cancer cell lines that were having various levels of EGFR and HER2 receptor expressions [5]. Regardless of the above mentioned applications of Gefitinib, another use of Gefitinib is against the development of cancer in upper aerodigestive tract [6].


GEFITINIB: CLINICAL TRIALS
During the Gefitinib clinical trial of phase I, its different properties were observed and analyzed including the anti tumor potential, tolerability in patients having malignant solid cancers and the pharmacokinetics [7]. During the clinical trials of phase III based upon patients of advanced pulmonary adenocarcinoma those were previously untreated, the efficacy of Gefitinib EGFR inhibitor molecule was found to be much better than any other anti cancer agents like Paclitaxel and Carboplatin drugs and it was also recommended  as the very initial drug for the treatment [8]. Gefitinb is an orally administered drug showed the symptomatic progress in patients of brain metastasis [9]. In treatment of glioma, Gefitinib’s efficiency was got clear by the clinical studies of phase II based upon high Gefitinb concentrations that were successfully administered in GBM cancer tissues hence measuring the inhibition levels of EGFR phosphorylation by using specific assays for phosphorylation [10]. For this property Gefitinib EGFR inhibiting drug was also used for repeated GBM under clinical trials of phase II [11].
During the clinical trials phase II, Gefitnib’s different neoadjuvant doses combined with some other drugs or chemotherapeutic agents were applied on freshly diagnosed estrogen receptor positive breast cancer patients [12]. Two different doses of Gefitinib were also found to be evaluated in hormone refractory prostate cancer under the clinical trials phase II [13]. The potential role of Gefitinib in case of malignant nesothelioma was also studied by the company AstraZeneca during the clinical trials phase II hence Gefitinib is now recommended as a first-line therapy (NCT00787410).


GEFITINIB: TREATMENT OF NSCLC
In case of treatment of lung cancer the very most successful clinical studies of Gefitinib has shown good effects on patients suffering NSCLC [14]. An assessment of Gefitinib in phase II clinical trials as alone agent or combined with other chemotherapeutic agents was also carried out for treating the already treated NSCLC patients [15]. A combination of Erlotinib and Gefitinib is highly effective for the adenocarcinoma patients having no smoking background [16]. Another trial of phase III has proved the remarkable results of Gefitinib against the advanced NSCLC [17]. Some other trials of phase III to treat formaly treated patients of NSCLC by using Docetaxel has shown that Gefitinib’s superiority over it [18].

 

REFERENCES:
1. Yoshimasu, T.e.a., Histoculture drug response assay for gefitinib in non-small-cell lung cancer. General Thoracic and Cardiovascular Surgery, 2007.
2. TETSUYA, S.e.a., A Specific and Sensitive Assay for Gefitinib Using the Enzyme-Linked Immunosorbent Assay in Human Serum. Biol Pharm Bull, 2005.
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.
 

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S1025 Gefitinib (ZD1839) Gefitinib (ZD-1839, Iressa) 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. (484) (14)

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