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GEFITINIB – EGFR REGULATOR IN LUNG CANCER

by Selleckchem | Apr 12 2012

PROPERTIES OF GEFITINIB AND MECHANISM OF ACTION:
Teva and AstraZeneca are the manufacturing and marketing companies of Gefitinib. Gefitinib EGFR (HER) inhibitor is a strong and efficient compound that has undergone clinical evaluations. An anilinoquinazoline ring is present in the structure of Gefitinib. For a 1 gram package the price for Gefitinib is about $80 due to this reasonable cost its easier to buy Gefitinib. If someone wants to order Gefitinib for research or laboratory uses one can contact any of Gefitinib suppliers. It can be stable for 2 years if properly stored at -20 oC. For proper inhibition of Tyr992and Tyr1173 Gefitinib IC50 is 57nM and 37nM respectively for EGFR inhibition. Different Gefitinib assays are done to analyze the pharmacokinetics, sensitivity and effect of this agent and those assays were based on certain predictive markers such as EGFR mutated gene, K-Ras mutations and copy number. In routine researchers use HDRA (histoculture drug response assay) [1] or ELISA (enzyme linked immunosorbent assay) of human serum [2] in order to analyze its pharmacokinetics studies. The mechanism behind the actions of Gefitinib is the binding of this compound competitively with EGFR ATP-binding site in cancer cells surface hence resulting in the inhibition of EGFR tyrosine phosphorylation induced by ligand to check downstream pathways.

IN VIVO AND IN VITRO STUDIES OF GEFITINIB:
The combine effects of Gefitinib and Herceptin when applied to the human primary monolayers of breast cancer expressing ErbB-2 and EGFR resulted in positive results for the future [3]. These studies are confirmed by independent research groups where ability of Gefitinib to check the proliferation of those cells which have high EGFR expression and also in moderate expression of EGFR and high expression of ErbB-2 [4]. Antiapoptotic effects of Gefitinib are also studied in cell lines of breast cell lines having various amounts of HER2 and EGFR receptor expression [5]. Aside from the above application of Gefitinib, Its another use is for against upper aerodigestive tract cancers development [6].

CLINICAL TRIALS OF GEFITINIB:
During clinical trials phase I of Gefitinib various properties were studied including anticancer potential, pharmacokinetics and tolerate ability in patients with malignant solid tumors [7]. Openly, during phase III studies based on previously untreated patients with advanced pulmonary adenocarcinoma, the efficiency of Gefitinib was much better than other anticancer drugs like Carboplatin and Paclitaxel and it was recommended as initial drug for treatment [8]. Gefitinib that is orally available agent showed symptomatic progress in brain metastasis patients [9]. In glioma treatment Gefitinib efficacy was cleared by phase II studies based on high concentration of this compound which was administered successfully in GBM tumor tissue following the measurement of EGFR phosphorylation inhibition by specific phosphorylation assays [10]. Due to this property Gefitinib has been applied for repeated GBM in phase II clinical trials [11].
During clinical phase II evaluation various neoadjuvant doses of Gefitinib were applied in a combination with other agents for patients with freshly diagnosed breast cancer with estrogen receptor positive [12]. In hormone refractory prostate cancer two various doses of Gefitinib were also evaluated during phase II trials [13]. The Gefitinib potency in malignant nesothelioma was also assessed by the AstraZeneca Company in phase II of clinical trials and due to these studies Gefitinib is recemmmended as first-line therapy (NCT00787410).

TREATMENT OF NSCLC AND BYOND:
In lung cancer treatment the most successful clinical trials of Gefitinib showed good actions on patients with NSCLC [14]. A clinical phase II assessment for Gefitinib as alone or in combination with other agents was done for treatment of already treated advanced patients of NSCLC [15]. The effects on non smoker patients of adenocarcinoma were highly positive when Erlotinib was used with Gefitinib [16]. A phase III evaluation reported about results of Gefitinib treatment for advanced NSCLC [17]. For treatment of formerly treated NSCLC patients with Docetaxel showed Gefitinib superiority during clinical trials phase III studies [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.