GEFITINIB – REFGULATING EGFR in CANCER

Introduction: The HER (EGFR) pathway and Gefitinib

Protein kinases have been established in recent years as prime targets for selective inhibition in many disorders involving cell proliferation or cell migration. The extent of the protein kinase system is very large with hundreds of different proteins interacting together to send multitude of signals to nuclei determining growth, death, transcription or response to any form damage or stress. To enable understanding of the mechanism of action for all these proteins they have been classified under pathways which are directly related. One of these pathways that is significant in its effects is the HER pathway, originally known as the EGFR pathway in relation to the epithelial growth factor [1-4]. However, more proteins related to EGFR were recognized (ErRB 2-4) and the HER family was born. The location of this series of proteins is too span across the cell membrane from the extracellular region (head) into the cytosole (tail). Attachment of ligands to the extracellular sites cause structural changes to the protein which expose tyrosine kinase binding domains in the section of the protein located in the cytosole. [1;5;6]. Auto-phosphorylation occurs which initiates activity, protein are attracted to the binding domain where phosphorylation occurs transferring the conformational change to the next protein in the desired sequence. This cascade continues until the signal reaches the correct part of the nucleus whereby the program function occurs be it life or death. [7]. Of the many possible pathways that could be triggered the PI-3K, the RAS or the JAK pathway are the most significantly affected. Since these pathways are heavily involved in the regulation of the cell proliferation, migration or apoptotic events they are prime targets for an inhibitory intervention [4;8]. Gefitinib was designed specifically for this purposes based on the structure and Clinical experience of Imatinib [9;10].

Gefitinib: Properties and Availability

The Gefitinib EFGR inhibitor has been approved for use in NSCLC after failure of first line platinum treatment since 2003. It is manufactured and marketed by AstraZenica using the product name Iressa but it has been also researched under the code ZD1839. The Gefitinib structure consists of an anilinoquinazoline containing both a chloro and a fluoro substitution. Gefitinib is a specific inhibitor of EGFR with Gefitinib IC50 of approximately 0.4nM. Gefitinib had a much less potent activity against ErbB-2 (0.87 µM) and ErbB-4 (1.1 µM) [11], gefitinib has also demonstrated significant activity against EGFR mutations EGFR^T1173 and EGFR^T992 with IC50’s in the 40-50 nM range [12]. Gefitinib solubility in DMSo is fair up to a maximum of 100mg/ml but is considered poorly soluble in both water and ethanol. Gefitinib stability of the solid form -20^oC is reported as being good, expiration of 2 years is recommended. Laboratories can buy Gefitinib from several reliable Gefitinib suppliers, however Gefitinib cost can be variable since Gefitinib prices can range from $89 up to $900.

Gefitinib: Preclinical investigations

Initial investigations with Gefitinib revealed reversible growth inhibition in a wide range of tumor cell lines and tumor xenografts [13]. Further research established Gefitinib as a potent chemotherapy agent in prostate [14;15], pancreatic [16], NSCLC [17;18] and breast cancer [19-22]. Cell type correlation demonstrated that HER2 over expressing cell lines were more sensitive to gefitinib treatment [23]. An investigation into 23 NSCLC cell lines demonstrated that gefitinib had significant anti-tumor activity in certain cell lines that correlated to EGFR copy number and EGFR gene mutations. With extensive research into the anti-tumor activities of gefitinib fast track approval was applied for and achieved in 2003 for NSCLC. However, in 2005 this approval was restricted to patients whom had already shown benefit for the treatment or already enrolled in a clinical trial. The reason for this restriction was due to two phase III trials cited prospectively in the original approval failed to meet their end points [24-26].

Gefitinib: Clinical status after NSCLC

There are multiple Gefitinib clinical trials in a variety of tumor types. Gefitinib is demonstrating clinical benefits in combinational therapy with previous chemotherapy drugs but as a single agent gefitinib consistently fails to meet target end points. The difference between in vitro and in vivo evidence is currently unexplained but several reports indicate that pharmacokinetic [27;28] / pharamcodynamic [27] / pharamcogenomic [29-31] issues may lie behind these problems.

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