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GEFITINIB; AN EGFR INHIBITOR

PROPERTIES AND MODE OF ACTION
Gefitinib is one of several tyrosine kinase inhibitors that are quite efficient in their activity. Gefitinib is actually an EGFR inhibitor. It is marketed by the two companies i.e., Teva and AstraZeneca. Gefitinib EGFR inhibitor is a strong inhibitory compound and Gefitinib structure shows the presence of a ring in it i.e., anilinoquinazoline. One can buy Gefitinib in the form of a 1 gm vial in approximately $80. Scientists can purchase Gefitinib for research or treatment purposes. Gefitinib solubility can be achieved in organic solvents like ethanol, DMSO and DMF and Gefitinib stability for approximately 2 years can be achieved if it is stored at -20 oC. Gefitinib IC50 for EGFR inhibition against Tyr 992 and Tyr 1173 is 37 nM and 57 nM respectively. Different types of assays have been designed to clinically analyze the pharmacokinetics and sensitivity of the drug. These assays are based upon some predicting markers e.g., EGFR mutated genes, copy number or K-Ras mutations. The assays that are routinely used to analyze human serum are enzyme linked immunosorbent assay or ELISA [1] and histoculture drug response assay or HDRA [2]. As far as mechanism of action of Gefitinib is concerned it binds competitively to the ATP-binding site of the EGFRs and inhibits ligand binding, hence inhibiting signal transduction resulting from the binding of ligand with the receptor.


STUDIES RELATED TO GEFITINIB
Gefitinib has been studied for use against different types of cancerous conditions as a single agent or in combination with other drugs and positive results were scene in many cases. Combined with Herceptin, the drug was used in human breast cancer primary monolayers that were expressing ErbB-2 and EGFR [3]. The results obtained were also confirmed by different groups of researchers independently. Gefitinib was also used to study the effect of different levels of expression of EGFR with high ErbB-2 on cell proliferation [4]. The drug was also studied as antiapoptotic agent by observing its effect on cell line of breast cancer with different expression levels of both receptors i.e., HER2 and EGFR [5]. Besides its role against breast cancer, Gefitinib has also been studied to be effective against cancer development in aerodigestive tract in the upper side [6].
 

CLINICAL TRIALS OF GEFITINIB
Different properties of Gefitinib have been studied in various Gefitinib clinical trials. In its phase I clinical trial the properties like anti-tumor potential, pharmacokinetics and tolerability in the patients with malignant solid tumors were observed [7]. The efficacy of Gefitinib EGFR inhibitor in the untreated patients of pulmonary adenocarcinoma in advanced stages was observed in clinical trial phase III and was recommended to be used as a very first drug for treatment as it was found quite better than existing agents against this cancer e.g., Paclitaxel and Carboplatin [8]. This drug is administered orally and shows progress in symptomatic manner in the patients of metastasis in brain [9]. The efficiency of the drug was studied against the Glioblastoma multiforme in clinical trial phase II after successful administration into the patients and assaying of the inhibition level after that [10]. Due to this property Gefitinib was also studied in clinical trial phase II against repeated GBM [11].
In a combinatorial therapy, neoadjuvants of the drug in combination with other drugs were administered in newly diagnosed breast cancer patients having positive estrogen receptors [12]. In hormone refractory type of prostate cancer doses of two different amounts were evaluated in phase II clinical trial [13]. Gefitinib was suggested as a first line therapy after studies by AstraZeneca in clinical trial of phase II on malignant nesothelioma (NCT00787410).


GEFITINIB IN NSCLC
Gefitinib has shown quite efficient results against the patients of Non small cell lung cancer or NSCLC [14]. Its effects as a single agent or in combination with other drugs was also studied for the same disease i.e., NSCLC [15]. In case of patients of adenocarcinomas with a background of no smoking, Gefitinib was found to be successful when combined with Erlotinib [16]. In other clinical trial in phase III the drug was seen to have good efficacy against NSCLC [17]. Gefitinib has been shown to be superior to Docetaxel, a drug used formally to treat NSCLC patients, in a study in clinical trial phase III [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.

 

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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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