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Hyun Chang, Ji Hea Sung, Sung Ung Moon, Han Soo Kim, Jin Won Kim, Jong Seok Lee
PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes...
January 2017: Yonsei Medical Journal
Lin Mu, Tianjiao Wang, Yanwei Chen, Xinqiang Tang, Yuhui Yuan, Yongshun Zhao
Glioblastoma multiforme (GBM) is the most common and severe form of primary tumor in the central nervous system of adults which has poor prognosis and limited therapeutic options. Epidermal growth factor receptor (EGFR) inhibitor, such as gefitinib (brand name Iressa, ZD1839), has been approved as a targeted medicine for several types of tumor including glioblastoma multiforme. However, gefitinib exerted very limited effects on some glioblastoma multiforme patients after a period of treatment due to intrinsic and acquired drug resistance...
October 2016: International Journal of Oncology
Xiaobo He, Yang Zhang, Yuxiang Ma, Ting Zhou, Jianwei Zhang, Shaodong Hong, Jin Sheng, Zhonghan Zhang, Yunpeng Yang, Yan Huang, Li Zhang, Hongyun Zhao
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as standard therapies for advanced nonsmall cell lung cancer (NSCLC) patients with EGFR mutation positive. Because these targeted therapies could cause tumor necrosis and shrinkage, the purpose of the study is to search for a value of optimal tumor shrinkage as an appropriate indicator of outcome for advanced NSCLC.A total of 88 NSCLC enrollees of 3 clinical trials (IRESSA registration clinical trial, TRUST study and ZD6474 study), who received Gefitinib (250 mg, QD), Erlotinib (150 mg, QD), and ZD6474 (100 mg, QD), respectively, during December 2003 and October 2007, were retrospectively analyzed...
August 2016: Medicine (Baltimore)
Can Zhao, Shu-Yan Han, Ping-Ping Li
Gefitinib (Iressa, AstraZeneca) has been widely used for the treatment of locally advanced or metastatic non-small cell lung cancer. A number of studies have been reported on its pharmacokinetics profiles, especially on the metabolism. In this review, we have comprehensively summarized the pharmacokinetic characteristics of gefitinib: absorption, distribution, metabolism and excretion (ADME). Overall, gefitinib reached the maximum plasma level relatively fast and distributed extensively. It underwent extensive biotransformation and predominantly excreted in feces, with less than 7% in the urine...
2017: Current Drug Delivery
Chien-Chang Huang, Cheng-Che Lee, Hsiao-Han Lin, Jang-Yang Chang
EGF-mediated EGFR endocytosis plays a crucial role in the attenuation of EGFR activation by sorting from early endosomes to late endosomes and transporting them into lysosomes for the final proteolytic degradation. We previously observed that cathepsin S (CTSS) inhibition induces tumour cell autophagy through the EGFR-mediated signalling pathway. In this study, we further clarified the relationship between CTSS activities and EGFR signalling regulation. Our results revealed that CTSS can regulate EGFR signalling by facilitating EGF-mediated EGFR degradation...
2016: Scientific Reports
Manisha Yadav, Abhishek Kumar Singh, Harish Kumar, Geeta Rao, Bandana Chakravarti, Anagha Gurjar, Shalini Dogra, Sapana Kushwaha, Achchhe Lal Vishwakarma, Prem Narayan Yadav, Dipak Datta, Anil Kumar Tripathi, Naibedya Chattopadhyay, Arun Kumar Trivedi, Sabyasachi Sanyal
BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) is used for treating non-small cell lung cancer. Gefitinib also induces differentiation in acute myeloid leukemia (AML) cell lines and patient samples lacking EGFR by an unknown mechanism. Here we dissected the mechanism of gefitinib action responsible for its EGFR-independent effects. METHODS: Signaling events were analyzed by homogenous time-resolved fluorescence and immunoblotting...
October 2016: Biochimica et Biophysica Acta
Mikkel Staberg, Signe Regner Michaelsen, Louise Stobbe Olsen, Mette Kjølhede Nedergaard, Mette Villingshøj, Marie-Thérése Stockhausen, Petra Hamerlik, Hans Skovgaard Poulsen
BACKGROUND: For Glioblastoma (GBM) patients, a number of anti-neoplastic strategies using specifically targeting drugs have been tested; however, the effects on survival have been limited. One explanation could be treatment resistance due to redundant signaling pathways, which substantiates the need for combination therapies. In GBM, both the epidermal growth factor receptor (EGFR) and the notch signaling pathways are often deregulated and linked to cellular growth, invasion and angiogenesis...
2016: Cancer Cell International
Dickran Kazandjian, Gideon M Blumenthal, Weishi Yuan, Kun He, Patricia Keegan, Richard Pazdur
On July 13, 2015, the FDA approved gefitinib (Iressa; AstraZeneca UK Limited) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Concurrently, a labeling expansion of the therascreen EGFR RGQ PCR Kit (Qiagen) as a companion diagnostic test was approved. The approval was based on the results of a multicenter, single-arm, open-label clinical study of 106 treatment-naïve patients with metastatic EGFR mutation-positive NSCLC who received gefitinib, 250 mg daily, until disease progression or intolerable toxicity...
March 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Aby Joiakim, Patricia A Mathieu, Catherine Shelp, Julie Boerner, John J Reiners
CYP1A1 and CYP1A2 are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e., phosphorylated) forms of extracellular regulated kinases (ERKs) and the epidermal growth factor receptor (EGFR). Shifting to serum/EGF-deficient medium also enhanced TCDD-mediated induction of cytochrome P450 (CYP)1A1 Treatment of cells cultured in complete medium with the EGFR inhibitors gefitinib (Iressa), AG1478, and CI-1033 resulted in concentration-dependent reductions of active EGFR and ERKs, and increased CYP1A1 mRNA content ∼3- to 18-fold above basal level...
May 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Brian S Bogdanowicz, Matthew A Hoch, Megan E Hartranft
Purpose The approval history, pharmacology, pharmacokinetics, clinical trials, efficacy, dosing recommendations, drug interactions, safety, place in therapy, and economic considerations of gefitinib are reviewed. Summary Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer death. Platinum-based chemotherapy and tyrosine kinase inhibitors, such as erlotinib and afatinib, are recommended therapies for nonsmall cell lung cancer. The European Medicines Association based their approval of gefitinib on the randomized, multicenter Iressa Pan-Asia Study (IPASS, NCT00322452) and a single-arm study showing effectiveness in Caucasians (IFUM, NCT01203917)...
April 2017: Journal of Oncology Pharmacy Practice
B O Zhou, Jun Nie, Weidong Yang, Chenhong Huang, Y E Huang, Hongfei Zhao
Lung cancer is a malignancy with the highest incidence of morbidity and mortality worldwide. The lack of effective detection methods leads to the ineffectiveness of convetional therapy. The aim of the current study was to analyze the hydrothorax epidermal growth factor receptor (EGFR) mutation in patients with advanced non-small lung cancer (NSCLC) and malignant pleural effusion. A new method for clinical treatment was developed through a comparison of the difference of EGFR tyrosine kinase inhibitor (EGFR-TKI)-targeted therapy...
February 2016: Oncology Letters
Nan Zheng, Can Zhao, Xi-Ran He, Shan-Tong Jiang, Shu-Yan Han, Guo-Bing Xu, Ping-Ping Li
Gefitinib (Iressa) is the first oral EGFR tyrosine kinase inhibitor and it brings benefits to non-small cell lung cancer patients with EGFR mutation. In this study, a simple, rapid and credible high performance liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous quantification of gefitinib and its main metabolites M523595, M537194, M387783 and M608236 in NSCLC tumor-bearing mouse plasma. Sample extraction was done by protein precipitation using acetonitrile containing dasatinib as the internal standard...
February 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Oliver Gautschi, Carola Stadelmann, Franziska Aebersold-Keller, Katharina König, Reinhard Büttner, Lukas C Heukamp, Daniel Betticher, Christa Baumann, Katharina Buser, Antonello Calderoni, Adrian Casty, Giannicola DʼAddario, Claudius Irlé, Christoph Mamot, Rudolf Morant, Andreas Trojan, Erica Pellicioli, Sonja Jehle-Schwertfeger, Stefan Aebi, Joachim Diebold
BACKGROUND: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and unknown EGFR mutation status has recently been questioned. PATIENTS AND METHODS: We conducted a retrospective study of patients with unknown EGFR mutation status and long-term response (LTR) to gefitinib in the Swiss Iressa expanded access program (EAP). We assessed patient characteristics, and performed Sanger sequencing and next generation sequencing on archived tumor tissue...
2015: Oncology Research and Treatment
Youwei Bi, Jiexin Deng, Daryl J Murry, Guohua An
Gefitinib (Iressa) is a selective and potent EGFR tyrosine kinase inhibitor. It received an accelerated FDA approval in 2003 for the treatment of patients with nonsmall cell lung cancer (NSCLC) and represents the first-line therapy for NSCLC with EGFR mutations. In the work presented herein, the disposition of gefitinib was investigated extensively in mouse in both plasma and 11 organs (liver, heart, lung, spleen, gut, brain, skin, fat, eye, kidney, and muscle) after a single IV dose of 20 mg/kg. Gefitinib demonstrated extensive distribution in most tissues, except for the brain, and tissue to plasma partition coefficients (K pt) ranged from 0...
January 2016: AAPS Journal
Qiong Li, Daoxiang Zhang, Xiaoying Chen, Lei He, Tianming Li, Xiaoping Xu, Min Li
Gefitinib (Iressa, ZD-1839), a small molecule tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) pathway, is currently under investigation in clinical trials for the treatment of colorectal cancer (CRC). However, as known, some patients develop resistance to TKIs, and the mechanisms mediating intrinsic resistance to EGFR-TKIs in CRC have not been fully characterized. Resistance to EGFR inhibitors reportedly involves activation of signal transducer and activator of transcription 3 (STAT3) in glioma and lung cancer...
November 6, 2015: Scientific Reports
Minkyu Kim, Yongseo Park, Won-Yoon Chung, Kwang-Kyun Park, Mankil Jung
Novel saponins that retain a free carboxyl group at the C-17 position and various sugars linked at the C-3 position of hederagenin aglycone were synthesized via stereospecific glycosylation. Since these natural products represented by Pulsatilla saponin D (PSD) were obtained in very small amounts, the total synthesis developed in this paper will resolve this problem of scarcity. The two types of synthesized arabinose- and rhamnose-cored saponins showed potent anticancer activity against a human lung cancer cell line (A549), and most disaccharide moiety saponins possessed more potent anti-lung cancer activity...
2015: Chemical & Pharmaceutical Bulletin
Eun Mi Kim, Jong Kuk Park, Sang-Gu Hwang, Hong-Duck Um
Members of the Bcl-2 family are established regulators of cell death. However, recent studies have shown that they can also regulate cell migration, invasion, and cancer metastasis. These functions of cancer cells are promoted by pro-survival Bcl-2 proteins (Bcl-2, Bcl-XL, and Bcl-w) but are suppressed by pro-apoptotic members (Bax and Bak). We have previously shown that Bcl-w and Bcl-XL enhance the ability of respiratory complex-I to produce reactive oxygen species (ROS), stimulating the phosphoinositide 3-kinase (PI3K)-dependent invasion pathway...
January 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Yusuke Narita, Yukiko Matsushima, Takeru Shiroiwa, Koji Chiba, Yoichi Nakanishi, Tatsuo Kurokawa, Hisashi Urushihara
OBJECTIVES: The combination use of gefitinib and epidermal growth factor receptor (EGFR) testing is a standard first-line therapy for patients with non-small cell lung cancer (NSCLC). Here, we examined the cost-effectiveness of this approach in Japan. MATERIALS AND METHODS: Our analysis compared the 'EGFR testing strategy', in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the 'no-testing strategy,' in which genetic testing was not conducted and all patients were treated with standard chemotherapy...
October 2015: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
(no author information available yet)
No abstract text is available yet for this article.
September 2015: Cancer Discovery
Soudabeh Sabetian, Mohd Shahir Shamsir
BACKGROUND: Sperm-egg interaction defect is a significant cause of in-vitro fertilization failure for infertile cases. Numerous molecular interactions in the form of protein-protein interactions mediate the sperm-egg membrane interaction process. Recent studies have demonstrated that in addition to experimental techniques, computational methods, namely protein interaction network approach, can address protein-protein interactions between human sperm and egg. Up to now, no drugs have been detected to treat sperm-egg interaction disorder, and the initial step in drug discovery research is finding out essential proteins or drug targets for a biological process...
2015: BMC Systems Biology
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