Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently recommended by international guidelines as first-line treatment in patients with advanced EGFR-mutant non-small-cell lung cancer. With the availability of drugs, more and more patients choose EGFR-TKI treatment. However, pharmaceutical drugs used in clinical practice have side effects, such as diarrhea, paronychia, and hepatotoxicity. Mental or conscious disturbance has never been reported before. In our clinical center, we found that several patients with advanced lung adenocarcinoma developed a mental disorder or conscious disturbance after EGFR-TKI treatment. This situation has not previously been reported. We conducted a retrospective study of patients with advanced lung adenocarcinoma treated with EGFR-TKI who showed a mental disorder or conscious disturbance. We reported five cases of lung adenocarcinoma who developed a mental disorder or conscious disturbance after treatment with EGFR-TKI. The main ...
Chai, C.S. and Liam, C (2017) Resistance mechanisms causing first-line epidermal growth factor receptor-tyrosine kinase inhibitor treatment failure. Annals of Oncology, 28 (10). ISSN 1569-8041 ...
MOESM12 of STAT3 induces G9a to exacerbate HER3 expression for the survival of epidermal growth factor receptor-tyrosine kinase inhibitors in lung cancers
Title:Design and Synthesis of 4-substituted Quinazolines as Potent EGFR Inhibitors with Anti-breast Cancer Activity. VOLUME: 17 ISSUE: 6. Author(s):Marwa F. Ahmed* and Naja Magdy. Affiliation:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Department of Pharmacology and toxicology, Faculty of Pharmacy, Taif University, Taif 26571. Keywords:Breast cancer, EGFR TK, IC50, quinazolines, synthesis, design.. Abstract:Background: Cancer is a major health problem to human beings around the world. Many quinazoline derivatives were reported to have potent cytotoxic activity. Aims: Our aim in this work is the discovery of potent epidermal growth factor receptor (EGFR) inhibitors with anti-breast cancer activity containing 4-substituted quinazoline pharmacophore. Method: Novel series of 4-substituted 6,8-dibromo-2-(4-chlorophenyl)-quinazoline derivatives have been designed and synthesized. New derivatives were tested against MCF-7 (human breast carcinoma cell line) and ...
TY - JOUR. T1 - Erlotinib (OSI-774, Tarceva™), a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with chemotherapy for advanced non-small-cell lung cancer. AU - Hightower, Mary. AU - Belani, Chandra P.. AU - Jain, Vinay K.. PY - 2003/5. Y1 - 2003/5. UR - http://www.scopus.com/inward/record.url?scp=0038080166&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=0038080166&partnerID=8YFLogxK. U2 - 10.1016/S1525-7304(11)70302-3. DO - 10.1016/S1525-7304(11)70302-3. M3 - Article. C2 - 14599299. AN - SCOPUS:0038080166. VL - 4. SP - 336. EP - 338. JO - Clinical Lung Cancer. JF - Clinical Lung Cancer. SN - 1525-7304. IS - 6. ER - ...
TY - GEN. T1 - The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. AU - Eun, Ju Lee. AU - Jin, Ha Whang. AU - Nam, Kyeong Jeon. AU - Kim, Jin. PY - 2007/1. Y1 - 2007/1. N2 - Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes. Overexpression of the epidermal growth factor receptor (EGFR) and high levels of certain matrix metalloproteinases (MMPs) have been implicated in the development of squamous cell carcinoma of oral cancer. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is clinically used for cancer patients. This article attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level, and to characterize the effects of ZD1839 with regard to human OSCC cell ...
5,6-Dihydro-[1,2,4]triazolo[1,5-c]quinazolines. Message 1. Features of interactions between [2-(3-aryl-1H-1,2,4-triazole-5-yl)phenyl]amines, aliphatic and aromatic aldehydes
Clinical trials have shown that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) did not improve the survival of patients with EGFR-mutated non-small cell lung cancer (NSCLC) because of the high crossover of treatments. Realistically, the role of EGFR-TKIs in NSCLC with mutated EGFR is not well known. We retrospectively analysed data from patients with recurrent or metastatic NSCLC. Clinical prognostic factors were identified by Cox proportional hazards modelling. Among 503 patients, the median overall survival (OS) for all of patients was 11.7 months. Cox analysis showed that PS 0-1, recurrent disease, EGFR mutations, or EGFR-TKI treatment were associated with improved OS. In patients with EGFR-activating mutations, Cox analysis showed that patients with adenocarcinoma, recurrent disease, or EGFR-TKI treatment had significantly longer survival. Patients with EGFR-activating mutations who received EGFR-TKI therapy had a median OS of 24.3 months, which was significantly longer than
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment for EGFR-mutant nonsmall cell lung cancer (NSCLC) patients. However, studies have reported that not all NSCLC patients harboring kinase domain mutations in epidermal growth factor receptor (EGFR) show significant clinical benefits from EGFR-targeted tyrosine kinase inhibitors (TKIs). Therefore, it is necessary to establish feasible biomarkers to predict the prognosis of EGFR-mutant NSCLC patients treated with EGFR-TKIs. This study aimed to determine biomarkers using inflammatory parameters from complete blood counts to predict the prognosis of EGFR-mutant NSCLC patients treated with EGFR-TKIs.We retrospectively investigated 127 stage IIIB/IV NSCLC patients with activating EGFR mutations who were treated with EGFR-TKIs. We used receiver operating characteristic (ROC) curves to determine the optimal cut-off for the inflammatory markers as prognostic factors. Additionally, univariate and ...
TY - JOUR. T1 - The benefits of achieving stable disease in advanced lung cancer. AU - Kelly, Karen. PY - 2003/7. Y1 - 2003/7. N2 - The cytostatic, molecular-targeted therapies becoming available for lung cancer and other human solid tumors are more likely to result in stable disease than to produce tumor regression. In the setting of advanced lung cancer, stable disease provides significant benefit to the patient. However, in the context of clinical trials, stable disease is vaguely defined, difficult to measure, and may represent a heterogeneous patient population. The inclusion of alternative trial end points such as symptom improvement and biologic activity may help to identify patients who have achieved clinically relevant stable disease. The epidermal growth factor receptor-tyrosine kinase inhibitor gefitinib (Iressa) has been shown to produce partial responses and stable disease in patients with advanced lung cancer who have previously received treatment with standard chemotherapies. In ...
Human being cytomegalovirus (HCMV) is a significant human being pathogen frequently connected with life-threatening disease in immunosuppressed individuals and newborns. contaminated cells. Quinazolines particularly inhibited viral early-late proteins synthesis but experienced no results at other phases from the replication routine, such as for example viral entry, in keeping with a blockage from the pUL97 function. As opposed to epithelial development element receptor inhibitors, quinazolines affected HCMV replication even though these were added hours after disease adsorption. Therefore, our results indicate that quinazolines are extremely effective inhibitors of HCMV replication in vitro by focusing on pUL97 proteins kinase activity. Human being cytomegalovirus (HCMV) is one of the family members and is connected with severe types of human being disease (23). Main acute infection aswell as lifelong prolonged infection from the sponsor ultimately causes multiple pathological effects which, ...
2014 SCI Comparison of targeted next-generation sequencing with conventional sequencing for predicting the responsiveness to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in never-smokers with lung adenocarcinoma: Lung cancer. 85(2):161~167 (3.737 ...
TY - JOUR. T1 - A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01). AU - Kim, Hye Ryun. AU - Jang, Joung Soon. AU - Sun, Jong Mu. AU - Ahn, Myung Ju. AU - Kim, Dong Wan. AU - Jung, Inkyung. AU - Lee, Ki Hyeong. AU - Kim, Joo Hang. AU - Lee, Dae Ho. AU - Kim, Sang We. AU - Cho, Byoung Chul. PY - 2017. Y1 - 2017. N2 - We aimed to evaluate the efficacy of dual inhibition of epidermal growth factor receptor (EGFR) with nimotuzumab (EGFR monoclonal antibody) plus gefitinib (EGFR-tyrosine kinase inhibitor) in advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy. An open label, randomized, phase II trial was conducted at 6 centers; 160 patients were randomized (1:1) to either gefitinib alone or nimotuzumab (200 mg, i.v. weekly) plus gefitinib (250 mg p.o. daily) until disease progression or intolerable toxicity. The primary endpoint was progression-free ...
291457567 - EP 1243582 A1 2002-09-25 - QUINOLINE AND QUINAZOLINE DERIVATIVES AND DRUGS CONTAINING THE SAME - There are provided compounds which can be used in the treatment of diseases mediated by the autophosphorylation of a PDGF receptor, specifically, compounds which can inhibit neointima formation hypertrophy. The compounds are those represented by formula (I) or pharmacologically acceptable salts or solvates thereof: CHEM wherein R 1 and R 2 represent hydrogen, alkyl or the like; R 3 , R 4 , R 5 , and R 6 represent hydrogen, halogen, alkyl, alkoxy or the like; R 11 and R 12 represent hydrogen, alkyl, alkylcarbonyl or the like; and A represents any one of formulae (i) to (x), provided that compounds wherein R 3 , R 4 , R 5 and R 6 represent hydrogen and A represents group (v) wherein u is 0 (zero) and R 19 represents phenyl optionally substituted by halogen, alkyl, or alkoxy are excluded.[origin: EP1243582A1] There are provided compounds which can be used in the treatment of diseases
Abstract. A phase III clinical trial showed gemcitabine chemotherapy combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib significantly improved overall survival in patients with advanced pancreatic cancer. Therefore, we studied whether addition of gemcitabine to erlotinib in cancer cells having intrinsic or acquired erlotinib resistance could restore chemosensitization in these cells. We studied the synergistic effect of erlotinib and gemcitabine in EGFR-overexpressing A-431 cells with acquired erlotinib resistance and in intrinsic erlotinib-resistant triple negative breast cancer (TNBC) BT-549, MDA-MB-231 and MDA-MB-468 cell lines. Erlotinib and gemcitabine were synergistic in both parental intrinsically erlotinib-sensitive A-431 cells (combination index = 0.69 at the effective dose [ED50]) and in two A-431 cell pools that had acquired erlotinib resistance (combination indices = 0.63 and 0.49 at ED50). The synergistic effect of erlotinib and gemcitabine on ...
Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl; R1 = OH, halo, alkyl, etc.; R2, R3 = independently H, (halo)alkyl, aminocarbonylalkyl, etc.; n = 0-3; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2-chloro-4-(4-methylpiperazin-1-yl)quinazoline with N-methyl-4-chlorobenzenesulfonamide gave II in 10% yield. The radioligand binding assay showed II having Ki of 200 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimers disease, schizophrenia, obesity or Parkinsons disease. [on SciFinder(R)]. ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
A compound of formula (I) wherein A, X, Y, Z, R.sub.1 and R.sub.24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, I.sub.Kur-associated disorders, and other disorders mediated by ion channel function. ##STR00001##
Gabriella M. Nepomuceno, Katie M. Chan, Valerie Huynh, Kevin S. Martin, Jared T. Moore, Terrence E. Obrien, Luiz A E Pollo, Francisco J. Sarabia, Clarissa Tadeus, Zi Yao, David E. Anderson, James B. Ames, Jared T. Shaw ...
Gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, is under clinical testing and use in cancer patients, including glioma. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma remain largely uncharacterized. Gefitinib inhibits cell growth and induces apoptosis in human glioma cells. Gefitinib also induces death of H4 cells with characteristics of the intrinsic apoptotic pathway, including Bax mitochondrial translocation, mitochondrial outer membrane permeabilization, cytochrome c cytosolic release, and caspase-9/caspase-3 activation. The importance of Bax in mediating gefitinib-induced apoptosis was confirmed by the attenuation of apoptosis by Bax siRNA and Bax channel blocker. Gefitinib caused Bad dephosphorylation, particularly in serine-112, and increased its binding preference to Bcl-2 and Bcl-xL. The dephosphorylation of Bad in gefitinib-treated cells was accompanied by reduced intracellular cyclic AMP content and protein
p,,b,INTRODUCTION: ,/b,The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial for first-line treatment of advanced EGFR mutation-positive NSCLCs. Afatinib and gefitinib costs and patients outcomes in France were assessed.,/p,,p,,b,METHODS: ,/b,A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation-positive NSCLCs. Outcomes and safety were taken primarily from the LUX-Lung 7 trial. Resource use and utilities were derived from that trial, an expert-panel questionnaire, and published literature, limiting expenditures to direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated over a 10-year time horizon for the entire population, and EGFR exon 19 deletion or exon 21 L858R mutation (L858R) subgroups. Deterministic and probabilistic sensitivity analyses were ...
AstraZeneca has inked a global license agreement with Synairgen, a U.K. company specializing in respiratory diseases, for SNG001, a novel, inhaled interferon beta (IFN-beta) in clinical development for treating respiratory tract viral infections in patients with severe asthma. SNG001 supports the immune system by correcting a deficiency which makes patients vulnerable to respiratory tract viral infections.. AstraZeneca will pay Synairgen a $7.25 million up-front fee and potential development, regulatory and commercial milestones of up to $225 million. In addition, AstraZeneca will pay tiered royalties ranging from single-digit up to mid-teens on commercial sales. AstraZeneca will be responsible for future development costs.. In early 2015, AstraZeneca will commence a phase IIa study in patients with severe asthma, building on available clinical data from an initial phase lla trial in a broad asthma population. SNG001 also provides the opportunity to expand the clinical program in other pulmonary ...
BRATISLAVA, Slovakia (AP) - Slovakias health minister says he plans to keep AstraZeneca in the countrys vaccine arsenal, speaking a day after the country suspended use of the shots after a recipient died.. Slovakia on Tuesday halted use of the two-shot AstraZeneca vaccine after its State Institute for Drug Control concluded last week that the death of a 47-year-old woman who received the AstraZeneca was likely linked to the vaccine.. AstraZeneca is still being administered, however, to those who have already gotten the first dose and are awaiting a second shot. Its currently being given to people between the ages of 18 and 44. Health Minister Vladimir Lengvarsky said the cause of womans death was still under investigation. He said another, and the main reason, for the suspension was that Slovakia does not have enough AstraZeneca shots to continue their administration.. Slovakia, like other members of the European Union, have seen a drop in deliveries from the company.. We still count on ...
Epithelial-mesenchymal transition (EMT) is normally one particular mechanism of possessed resistance to inhibitors of the skin growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). micro-RNA-200c, which can regulate ZEB1 adversely, was decreased in HCC4006EUr cells significantly. Our outcomes recommend that elevated can get EMT-related obtained level of resistance to EGFR-TKIs in NSCLC. Tries should end up being produced to explore concentrating on to resensitize TKI-resistant tumors. Launch Despite the advantage of skin development aspect receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancers (NSCLC) sufferers with mutation [1], obtained level of resistance to these therapies is normally a vital scientific issue. Although the Testosterone levels790M supplementary mutation [2] and gene amplification [3] may jointly accounts for 70% of this level of resistance, systems for the staying 30% are unsure. The epithelial-mesenchymal ...
Objectives and Background To reveal the details system of miR-484 in myocardial ischemia-reperfusion (MI/R) damage. appearance of caspase-3/9 had been elevated in IR-C group. Weighed against the I/R Slc2a4 and IR-C groupings, the apoptotic index of myocardial cells in the ischemic area was reduced, the membrane potential was elevated, as well as the expression of caspase-3/9 was decreased in the miR group significantly. SMAD7 was the mark gene of miR-484. Conclusions MiR-484 protected myocardial cells from We/R damage by suppressing caspase-9 and caspase-3 appearance during cardiomyocyte apoptosis. MiR-484 decreased the appearance of IL-6, TNF-, and IL-1 in MI/R. MiR-484 might alleviate the decreasing of mitochondrial membrane potential in MI/R cells. Keywords: Apoptosis, Mitochondrial membrane potential, Caspase-3, Caspase-9 Launch Ischemia-reperfusion (I/R) damage is the injury caused when blood supply returns to the tissue after a period of ischemia. It is a Pyrazinamide complex process ...
Gefitinib, as the first epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC), has been proved to significantly improve the progression-free survival (PFS) in the first-line setting but suffers from resistance 7-10 months after treatment initiation. Apatinib (YN968D1), a potent vascular endothelial growth factor receptor (VEGFR) 2-TKI, specifically binds to VEGFR2 and leads to anti-angiogenetic and anti-neoplastic effect. Concurrent inhibition of VEGFR and EGFR pathways represents a rational approach to improve treatment responses and delay the onset of treatment resistance in EGFR-mutant NSCLC. This ACTIVE study aims to assess the combination of apatinib and gefitinib as a new treatment approach for EGFR-mutant NSCLC as a first-line setting. This multicenter, randomized, double-blind, placebo-controlled phase III study (NCT02824458) has been designed to assess the efficacy and safety of apatinib or placebo
Lung cancer is the leading cause of cancer-related mortality for both men and women in United States and is estimated to remain the most fatal cancer-related malignancy (1). Little improvement in the efficacy of chemotherapy has been made in the last 20 years, usually attributed to the overexpression and overactivity of EGFR in NSCLC (4, 29-31). However, the use of selective EGFR tyrosine kinase inhibitors (gefitinib) and monoclonal antibodies against EGFR toward the treatment of lung cancer has continuously failed (32, 33). Therefore, additional alternative therapies with low toxicity and increased efficacy should be explored. Although recent studies suggest that nonpsychoactive synthetic cannabinoids possess antitumor effects against various tumors, including breast cancer, not much is known about the effects of synthetic CB1/CB2 agonists on NSCLC growth and metastasis. In the present study, we analyzed the antitumorigenic and antimetastasis effects of CB1/CB2 agonists Win55,212-2 and CB2 ...
Simotinib, also known as SIM6802, is a novel oral epidermal growth factor receptor tyrosine kinase inhibitor with potential anticancer activity. Simotinib has demonstrated equal or superior antineoplastic activities to erlotinib in preclinical studies.
The molecular mechanisms underlying erlotinib resistance in breast cancer have not been well defined. In our screening of breast cancer cell lines, down-regulation of CDK2 after treatment with erlotinib showed association with erlotinib sensitivity. Moreover, our study provides that erlotinib sensitivity is causally linked with CDK2 activity, indicating that erlotinib sensitivity depends, at least in part, on CDK2 activity. Some reports have indicated that the growth-inhibitory effect induced by EGFR-TKIs in sensitive cell lines depends mainly on G1 cell cycle arrest (1, 7, 11, 13); others have shown CDK2 activity to be down-regulated after treatment with an EGFR-TKI (12, 13). However, this is the first report establishing cause and effect relationship between erlotinib sensitivity and CDK2 activity.. The erlotinib sensitivity of breast cancer cell lines has clinical relevance for several reasons. The limited clinical activity of EGFR-TKIs in breast cancer was also echoed by the findings of this ...
Protein tyrosine kinase 2 (PTK2) expression has been reported in various types of human epithelial cancers including lung cancer; however, the role of PTK2 in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) has not been elucidated. We previously reported that pemetrexed-resistant NSCLC cell line PC-9/PEM also acquired EGFR-TKI resistance with constitutive Akt activation, but we could not find a therapeutic target. Cell viability in EGFR-mutant NSCLC cell lines was measured by the WST-8 assay. Phosphorylation antibody array assay for receptor tyrosine kinases was performed in PC-9 and PC-9/PEM cell lines. We evaluated the efficacy of EGFR and PTK2 co-inhibition in EGFR-TKI-resistant NSCLC in vitro. Oral defactinib and osimertinib were administered in mice bearing subcutaneous xenografts to evaluate the efficacy of the treatment combination in vivo. Both the PTK2 phosphorylation and the treatment combination efficacy were evaluated in erlotinib-resistant EGFR-mutant NSCLC
Product Description Product Description Erlotinib hydrochloride For Treat Non-small Cell Lung Cancer 183319-69-9 Erlotinib hydrochloride---------Basic info Product Name Erlotinib hydrochloride CAS 183319-69-9 MF C22H24ClN3O4 MW 429.9 Chemical Properties Off-White Solid Usage Selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor. Antineoplastic Erlotinib HCl is an HER1/EGFR inhibitor with IC50 of 2 nM. Erlotinib HCl (OSI-744) is an…
The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer. These agents are particularly effective in a subset of patients whose tumors harbor activati …
Monitor impact of Healthy Heart Africa programme and expand to other regions. AstraZeneca can evaluate the impact of its hypertension-focused Healthy Heart Africa programme in Kenya and consider expanding it to other non-communicable diseases (NCDs) and countries/regions. It can use the lessons learned from this programme to update its overall access strategy.. Broaden IP access strategy to include NCDs. AstraZeneca can expand the reach of programmes such as Healthy Heart Africa by licensing products for NCDs. For Healthy Heart Africa, this could include ticagrelor (Brilinta®), a first-line option for preventing atherothrombotic events. This could make AstraZeneca the first company to license a product targeting an NCD. A first step would be to explicitly include NCD products in its commitment to licensing.. Further expand partnerships with academia for R&D capacity building. AstraZeneca can build on its growing focus on academic partnerships in the UK to include public research organisations ...
Georgian health officials have decided to continue vaccination with AstraZeneca only for individuals over 55 years of age following statements from the European Medicines Agency and the World Health Organisation that say that unusual blood clots should be listed as a very rare side effect of the AstraZeneca vaccine for Covid-19, Trend reports citing Agenda.ge.. Today, the board of experts discussed and recommended continuing vaccination with AstraZeneca in the age group over 55, no further expansion will be made in terms of age group for AstraZeneca, Georgian deputy Health Minister Tamar Gabunia said.. She said that the delivery of the AstraZeneca vaccination will continue in Georgia as the circle of people over 55 is quite wide.. AstraZeneca has quite good results in the elderly, Gabunia added.. In the UK alone, as of March 31 there had been 79 reports of rare blood clots with low platelets, some in the brain, it was revealed on Wednesday. ...
HER2/ERBB2-overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for ,7,800 proteins, ,300 protein kinases, and ,15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an ...
Author Disclosures: T. Ueland: None. A. Åkerblom: Research Grant; Significant; AstraZeneca (institutional grant), Roche (institutional grant). T. Ghukasyan: Research Grant; Significant; AstraZeneca (institutional grant), Roche (institutional grant). A.E. Michelsen: None. P. Aukrust: None. R.C. Becker: Consultant/Advisory Board; Modest; Janssen (scientific advisory board member), AstraZeneca (scientific advisory board member), Portola (safety reviewing committee member), Merck. M. Bertilsson: Research Grant; Significant; AstraZeneca (institutional grant), Roche (institutional grant). A. Himmelmann: Employment; Significant; AstraZeneca. S.K. James: Research Grant; Significant; AstraZeneca (institutional grant), Abbot vascular (institutional grant), Roche (institutional grant). Honoraria; Modest; AstraZeneca, The Medicines Company, Bayer. Consultant/Advisory Board; Modest; AstraZeneca. A. Siegbahn: Research Grant; Significant; Bristol-Myers Squibb (institutional grant), AstraZeneca (institutional ...
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) harboring activating EGFR gene mutations. Although studies show an increased progression free survival (PFS) with use of EGFR TKIs in the first-line setting, most patients will develop resistance to therapy after the first about 10 months. Undoubtedly it is critical to choose an optimal clinical strategy for patients with EGFR sensitive mutation undergoing EGFR-TKI resistance. The second biopsy should be applied under condition permission to verify specific resistance mechanism. Here we discussed the mechanism of drug resistance and the choice of therapeutic regimen, also compared the superior and inferior of each treatment plan, which proposed a novel perspective for NSCLC target therapy.
Colon cancer is one of the most common human malignancies and the second leading cause of cancer death in North America just behind lung cancer. Advanced disease is associated with a poor prognosis and a 5-year survival rate of ,5% ( 35). 5-Fluorouracil with leucovorin has been the primary chemotherapy regimen for advanced colorectal cancer patients. New cytotoxic compounds are now available, including oral fluoropyrimidines, the topoisomerase I inhibitor, irinotecan (CPT-11), and the third-generation platinum compound oxaliplatin. However, these agents have not had dramatic effects on advanced disease. Novel approaches that selectively target deregulated molecular events in colon cancer cells are under development, such as targeting EGFR by monoclonal antibodies or small-molecule TKIs.. The currently available EGFR TKIs are structurally related to quinazoline, pyridopyrimidine, and pyrrolopyrimidine developed during the past decade ( 36). Quinazolines, such as AG1478, are potent EGFR ...
The EGFR pathway has been an attractive target because it is dysregulated in a significant fraction of malignant gliomas through overexpression, amplification, and activating mutations (Rich et al., 2004). Moreover, recent studies have demonstrated that EGFRvIII is required for tumor maintenance in glioma (Mukasa et al., 2010). The EGFR tyrosine kinase inhibitor gefitinib has been evaluated in a number of clinical trials for GBM; however, results have been disappointing (Rich et al., 2004; Lieberman et al., 2004). The failure of gefitinib raises questions pertaining to delivery of drug to its target. Active efflux at the BBB could prevent drugs from attaining therapeutic levels in the brain and is probably one of the main reasons behind resistance to chemotherapy. It has been shown that several other tyrosine kinase inhibitors are avid substrates for P-gp and BCRP and that their brain distribution is limited due to active efflux out of the brain (Dai et al., 2003; Chen et al., 2009; Lagas et ...
Prophylactic minocycline and reactive treatment are both acceptable options for treatment of erlotinib-induced rash in non-small cell lung cancer (NSCLC).
JoVE publishes peer-reviewed scientific video protocols to accelerate biological, medical, chemical and physical research. Watch our scientific video articles.
JoVE publishes peer-reviewed scientific video protocols to accelerate biological, medical, chemical and physical research. Watch our scientific video articles.
Purpose:Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant lung cancer cells by activating Met and the downstream PI3K/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. Experimental Design:The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR-mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion, and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into SCID mice and the therapeutic effects of E7050 plus gefitinib were assayed. ...
Purpose: The impact of epidermal growth factor receptor (EGFR) and KRAS genotypes on outcomes with erlotinib or gefitinib therapy continues to be debated. This study combines patient data from five trials in predominantly Western populations to assess the impact of EGFR and KRAS mutations on first-line therapy with an EGFR-tyrosine kinase inhibitor (TKI) and compare clinical versus molecular predictors of sensitivity.. Experimental Design: Chemotherapy-naïve patients with advanced non-small cell lung cancer and known EGFR mutation status treated with erlotinib or gefitinib monotherapy as part of a clinical trial were eligible for inclusion. Patients received daily erlotinib (150 mg) or gefitinib (250 mg) until disease progression or unacceptable toxicity. Data were collected in a password-protected web database. Clinical outcomes were analyzed to look for differences based on EGFR and KRAS genotypes, as well as clinical characteristics.. Results: Patients (223) from five clinical trials were ...
Anthony joined AstraZeneca in 2014, holding a wealth of experience in exploratory clinical development across the pharmaceutical industry and academia. In his role he has recruited world- leading MD.PhDs and significantly improved both translational clinical science and operations, such as clinical trial cycle times. He oversees the iDecide program including REACT which focuses on real time visualisation and analysis of clinical trial data, while incorporating patient perspectives. REACT allows AstraZeneca to improve clinical trial design and ultimately enables patients to receive medicines more quickly.. Anthony is a Fellow at Homerton College, University of Cambridge and, prior to AstraZeneca, was a Board Director for Cardioxyl (2012-2015) and Rgenix (2014-2015), and a Venture Partner at OrbiMed Advisors, a global healthcare-only investment firm (2012-2013). Preceding his life sciences investment experience, he led exploratory clinical development as Vice President, Discovery Medicine Clinical ...
London, March 23: A large trial in the US and two South American countries of the Oxford-AstraZeneca vaccine has shown 79 per cent efficacy rate at preventing symptomatic COVID-19 and 100 per cent effectiveness in stopping severe disease and hospitalisation, the biotech firm said.. A Phase III study of the vaccine, developed by Oxford University and produced by AstraZeneca was conducted by AstraZeneca plc in the US, Chile and Peru and reaffirmed that the vaccine is safe and highly effective , adding to previous trial data from the UK, Brazil and South Africa.. The Oxford/AstraZeneca vaccine is also being produced as part of a tie-up by the Serum Institute of India.. The vaccines efficacy was consistent across ethnicity and age, and in participants aged 65 years and over, its effectiveness was 80 per cent.. These results are great news as they show the remarkable efficacy of the vaccine in a new population and are consistent with the results from Oxford-led trials, said Andrew Pollard, Professor ...
Pfizer has announced a deal with AstraZeneca for exclusive over-the-counter (OTC) rights to market Nexium for approved indications in the United States, Europe and the rest of the world.. Under the terms of the agreement, Pfizer will make an upfront payment of $250 million to AstraZeneca, who will be eligible to receive milestone and loyalty payments based on product launches and sales.. Proton pump inhibitor, Nexium (esomeprazole magnesium), is a leading prescription drug currently approved to treat patients with the symptoms of gastroesophageal reflux disease (GERD). It was launched by AZ in Europe in 2000, and a year later in the US.. Nexium is one of the most recognised and respected products in its class with tremendous brand equity and loyalty. We are proud to be AstraZenecas partner of choice for OTC Nexium, said Paul Sturman, Pfizer Consumer Healthcare President.. By working with AstraZeneca to offer upon regulatory approval an over-the-counter version of Nexium - a brand people know ...
Health,...WILMINGTON Del. Nov. 25 /- AstraZeneca today... The agreement settles the patent infringement litigation filed by... The settlement agreement will allow Teva to commence sales of bude... AstraZeneca intends to continue to sell Pulmicort Respules even a...,AstraZeneca,Settles,US,Pulmicort,Respules,Patent,Litigation,with,Teva,medicine,medical news today,latest medical news,medical newsletters,current medical news,latest medicine news
Selective inhibition of tyrosine kinase activity is a promising strategy for cancer treatment. ZD1839 is one of the first tyrosine kinase inhibitors to be tested in patients with advanced solid tumors. Initial studies have shown promising results, and additional clinical trials are in progress to additionally define the activity and toxicities of this new treatment modality. We have been interested in how this agent inhibits the growth of tumor cells and which subset of tumors may be most effectively treated by this agent. In a survey of human tumor cell lines, we find that tumors with HER2 overexpression are particularly sensitive to ZD1839. There is no correlation with HER3 or HER4 expression. Although in vitro this agent shows the highest activity against EGFR, it is apparent from our analysis of two EGFR-overexpressing tumor types, MDA-MB-468 and A431, that overexpression of EGFR is not sufficient to determine sensitivity to ZD1839. It remains possible that the consequences of EGFR ...
TY - JOUR. T1 - The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. AU - Rho, Jin Kyung. AU - Choi, Yun Jung. AU - Lee, Jin Kyung. AU - Ryoo, Baek Yeol. AU - Na, Im Il. AU - Yang, Sung Hyun. AU - Lee, Seung Sook. AU - Kim, Cheol Hyeon. AU - Yoo, Young Do. AU - Lee, Jae Cheol. PY - 2009/10. Y1 - 2009/10. N2 - The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib- or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more ...
Title: Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and New Therapeutic Perspectives in Non Small Cell Lung Cancer. VOLUME: 12 ISSUE: 6. Author(s):Laura Bonanno, Antonio Jirillo and Adolfo Favaretto. Affiliation:Medical Oncology 2, Istituto Oncologico Veneto-IRCCS, Via Gattamelata, 64, 35128 Padova, Italy.. Keywords:EGFR, Tyrosine kinase inhibitors, resistance, mutations, amplifications, MET, VEGFR, NSCLC, Gefitinib, Erlotinib. Abstract: EGFR somatic mutations define a subset of NSCLCs that are most likely to benefit from EGFR tyrosine kinase inhibitors (TKIs). These tumors are dependent on EGFR-signaling for survival. Recently, tyrosine kinase domain somatic mutations have been approved as criterion to decide first-line therapy in this group of advanced NSCLCs. Anyway, all patients ultimately develop resistance to these drugs. Acquired resistance is linked to a secondary EGFR mutation in about a half of patients. Uncontrolled activation of ...
This trial will investigate the efficacy and tolerability of epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, in combination with
TY - JOUR. T1 - Disruption of ETV6 leads to TWIST1-dependent progression and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in prostate cancer. AU - Tsai, Yuan Chin. AU - Zeng, Tao. AU - Abou-Kheir, Wassim. AU - Yeh, Hsiu Lien. AU - Yin, Juan Juan. AU - Lee, Yi Chao. AU - Chen, Wei Yu. AU - Liu, Yen Nien. N1 - Funding Information: This work was supported by the Ministry of Science and Technology of Taiwan to YCT (MOST104-2320-B-038-055-MY3), WYC (MOST106-2320-B-038-057), and YNL (MOST104-2314-B-038-045-MY3 and MOST105-2628-B-038 -006 -MY3), by Taipei Medical University-Wan Fang Hospital to WYC (105TMU-WFH-04), by the National Health Research Institutes of Taiwan to YNL (NHRI-EX107-10702BI), and by the Health and Welfare Surcharge of Tobacco Products to YNL (MOHW106-TDU-B-212-144001).. PY - 2018/2/19. Y1 - 2018/2/19. N2 - Background: ETS variant gene 6 (ETV6) is a putative tumor suppressor and repressed by epidermal growth factor receptor (EGFR) signaling in prostate ...
Serotonin receptors play a variety of functional roles in the body. Some indications and treatment claims for one of the classes of serotonin receptors, the 5-HT3 receptor family, include: anxiety, depression, chemotherapy- and radiation-induced emesis, constipation, irritable bowel syndrome, pain, drug addiction, and satiety control. A 5-HT3 receptor partial agonist, MD-354, served as a lead compound in the development of new 5-HT3 receptor ligands. Using halogenated analogs the study investigated their effect on binding to the 5-HT3 receptor. Conformationally-constrained analogs (quinazolines) were shown to be a novel class of 5-HT3 receptor antagonists. The log P values were determined for several analogs, and indicated that these ligands should be able to penetrate the blood-brain barrier. A homology model of the 5-HT3 receptor was built and the docking modes were assessed for these two series. Quinazolines were investigated for antidepressant properties using the mouse tail suspension test, and
TY - JOUR. T1 - Complete response in gallbladder cancer to erlotinib plus gemcitabine does not require mutation of the epidermal growth factor receptor gene. T2 - A case report. AU - Mody, Kabir. AU - Strauss, Edward. AU - Lincer, Robert. AU - Frank, Richard C.. PY - 2010/10/20. Y1 - 2010/10/20. N2 - Background: Gallbladder cancer typically follows an aggressive course, with chemotherapy the standard of care for advanced disease; complete remissions are rarely encountered. The epidermal growth factor receptor (EGFR) is a promising therapeutic target but the activity of single agent oral EGFR tyrosine kinase inhibitors is low. There have been no previous reports of chemotherapy plus an EGFR-tyrosine kinase inhibitor (TKI) to treat gallbladder cancer or correlations of response with the mutation status of the tyrosine kinase domain of the EGFR gene.Case presentation: A 67 year old man with metastatic gallbladder cancer involving the liver and abdominal lymph nodes was treated with gemcitabine ...
Gefitinib and erlotinib were the first EGFR tyrosine kinase inhibitors (TKIs) that were approved for the treatment of patients with non-small cell lung cancer (NSCLC). These drugs inhibit kinase activity through competitively interacting with the ATP-binding site of EGFR, preventing autophosphorylation and consequently inhibiting downstream signaling. This inhibition leads to apoptosis in cells dependent on EGFR signaling, such as those with EGFR mutations.. Gefitinib efficacy was first evaluated in 2 single-arm phase II studies in patients with NSCLC who had received prior chemotherapy. The success of these trials led to the accelerated approval of gefitinib in 20034,5 and initiation of a phase III trial6 (ISEL), which randomized patients to gefitinib versus placebo and found no difference in median survival (5.6 vs. 5.1 months, respectively). The lack of an overall survival benefit in ISEL prompted the FDA to restrict gefitinib use. Notably, these early studies did not select or evaluate ...
TY - JOUR. T1 - Epidermal growth factor receptor (EGFR)-tyrosine Kinase inhibitor treatment and salvage chemotherapy in EGFR-mutated elderly pulmonary adenocarcinoma patients. AU - Tseng, Yen Han. AU - Tseng, Yen Chiang. AU - Lin, Yi Hsuan. AU - Lee, Yu Chin. AU - Perng, Reury Perng. AU - Whang-Peng, Jacqueline. AU - Chen, Yuh Min. PY - 2015/6/8. Y1 - 2015/6/8. N2 - Background. Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown. Materials and Methods. We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI ...
A number of different strategies have been explored to therapeutically modulate tumor oxygenation. The studies described here show that the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib improves oxygenation within A431 squamous cell carcinoma xenografts. Using in vivo PET imaging with the hypoxia marker FAZA, it was seen that treatment with gefitinib reduced hypoxia in A431 xenografts in comparison with untreated control tumors. Importantly, serial PET imaging studies were able to show that gefitinib reduced hypoxia compared with pretreatment levels. These findings were verified in a parallel experiment in which hypoxia was assessed using pimonidazole binding at time points corresponding with the PET studies.. In vivo imaging of hypoxia was conducted using the PET hypoxia imaging agent FAZA. This compound displays different physical properties to fluoromisonidazole, in particular, a lower octanol/water partition coefficient, indicating the potential for more rapid ...
Conventional chemotherapeutic regimens have reached an efficacy plateau against most solid tumors and deal with significant toxicity. Recently, the goal of the oncologic research to improve outcome and reduce treatment-related side-effects has led to the development of novel anticancer treatments targeting specific proteins or genes involved in cancer growth and progression. In particular, the tyrosine-kinase inhibitors (TKIs) gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have been approved for the treatment of non-small-cell lung cancer (NSCLC). Their clinical activity has been related to different clinical and biological parameters, such as the presence of activating mutations in the kinase domain of the target. Disappointingly, their clinical efficacy is limited by the development of resistance which is caused in more than 50% of the cases by the emergence of a secondary point-mutation (T790M) in the ATP-binding cleft of EGFR. Several novel EGFR inhibitors, ...
Lung cancer is the most common cause of cancer deaths in Korea [7]. Traditional therapy, including resection, platinum-based chemotherapy and radiation therapy, have only limited therapeutic value. Therefore, the 5-year survival rate of lung cancer has not changed significantly in the past 30 years [8].. EGFR TKI therapy, which specifically targets EGFR, was recently introduced and provided guidance in this situation. Targeting EGFR in patients with activating EGFR mutations has shown initial and significant success in practice [1]. Unfortunately, the vast majority of patients develop resistance to the treatment, typically in less than 1 year. In this situation, understanding the mechanism of the resistance became very important.. Most of the mechanisms that lead to EGFR TKI resistance involve an additional mutation, such as a T790M mutation, or amplification of alternative pathways. In addition, morphological transformation is also a well-known mechanism. The most well known example of this ...
TY - JOUR. T1 - Mechanisms and overcome of acquired resistance to EGFR tyrosine kinase inhibitors. AU - Soh, Junichi. AU - Toyooka, Shinichi. AU - Ueno, Tsuyoshi. AU - Miyoshi, Shinichiro. PY - 2012/4. Y1 - 2012/4. N2 - Development of effective therapies for non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, which account for approximately 40% of lung adenocarcinoma patients in Japan, is important to improve the clinical outcome of NSCLC. EGFR-mutant NSCLCs are sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and elucidating the binding affinity of adenosine triphosphate (ATP) and EGFR-TKI to wild type or mutant EGFR helps our understanding of the mechanisms of resistance to EGFR-TKI. The mechanisms of acquired resistance to EGFR-TKIs are broadly classified into two categories: 1) secondly acquired EGFR mutations including T790M and 2) oncogene kinase switch such as MET gene amplification. To overcome the acquired resistance, it is ...
Pharma company AstraZeneca has publicly released preclinical data from more than 50 of its medicines in order to find new drug combinations for cancer treatments. The data AstraZeneca released will be used in a competition it created in partnership with the DREAM Challenge, a non-profit, collaborative community that runs crowdsourcing efforts for biology.. People who participate in the challenge will develop computer models that identify the properties of drugs that make them powerful when combined. Anyone who has the training or expertise to work with these models is invited to participate. The winners of AstraZenecas challenge will be able to submit their prediction for publication in the journal Nature Biotechnology.. Other organizations that partnered with AstraZeneca for the challenge, which is called AstraZeneca-Sanger Drug Combination Prediction DREAM Challenge, include the Wellcome Trust Sanger Institute, the European Bioinformatic Institute, and Sage Bionetworks.. AstraZeneca has a ...
The EGFR TKI erlotinib was shown to result in increased survival in previous clinical trials when used as monotherapy in previously treated patients with advanced NSCLC [30]. Toxicity to erlotinib is markedly lower than many alternative pharmacologic treatments, and would clearly be a preferred therapeutic option if survival was shown to be equivalent or better than treatment with other second line agents. Since only a fraction of patients respond to such therapy, a priori identification of responders could have a vast effect on survival. Many clinical parameters which have been shown to correlate with response to EGFR TKIs, including smoking history, gender, ethnicity, and tumor histology. Additionally, EGFR expression levels, phosphorylation status of EGFR, and mutations within the kinase domain [22, 28, 31] also correlate with sensitivity to some degree. While each of these predictors of response result in some overlap, potential responders to EGFR targeted therapeutics may be overlooked. In ...
TY - JOUR. T1 - Sex difference in the influence of smoking status on the responsiveness to gefitinib monotherapy in adenocarcinoma of the lung. T2 - Okayama Lung Cancer Study Group experience. AU - Hotta, Katsuyuki. AU - Kiura, Katsuyuki. AU - Takigawa, Nagio. AU - Kuyama, Shoichi. AU - Segawa, Yoshihiko. AU - Yonei, Toshiro. AU - Gemba, Kenichi. AU - Aoe, Keisuke. AU - Shibayama, Takuo. AU - Matsuo, Keisuke. AU - Kamei, Haruhito. AU - Fujiwara, Yoshiro. AU - Bessho, Akihiko. AU - Moritaka, Tomonori. AU - Sugimoto, Keisuke. AU - Tabata, Masahiro. AU - Ueoka, Hiroshi. AU - Tanimoto, Mitsune. N1 - Copyright: Copyright 2009 Elsevier B.V., All rights reserved.. PY - 2009/1. Y1 - 2009/1. N2 - Background: Gefitinib is effective in patients with lung adenocarcinoma. Smoking status also affects the responsiveness to gefitinib, but it has not been fully evaluated whether a sex difference exists in the influence of smoking on the efficacy of gefitinib in patients with lung adenocarcinoma. Methods: We ...
Saccharin belongs to a class of cyclic sulfonamides and this is used as an artificial sweetener for a longtime. The benzothiazole and quinazoline derivatives form an important classes of fused heterocyclic compounds with a wide range of biological activities such as antimicrobial (Schwartz et al., 1992), anticancer (Wolfe et al., 1990), antiinflammatory (Tereshima et al., 1995). As a part of our studies in this area, the molecular and crystal structures of the title compound have been determined and the results are presented here.. The title compound comprises a benzothiazole ring fused with quinazoline ring. X-ray analysis confirms the molecular structure and atom connectivity as illustrated in Fig. 1. The benzothiazole ring system is essentially planar with a maximum deviation of -0.0127 (16)Å for the C7 atom. The quinazoline ring system is also essentially planar with the maximum deviation of -0.1588 (15)Å for the N1 atom. The dihedral angle between the benzothiazole and quinazoline ring ...
Results In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected EgfrΔepi versus Egfrfl/fl control mice. In H. pylori-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylori-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from EfgrΔepi versus Egfrfl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric ...
AMPRENAVIR EXPANDED ACCESS PROGRAM ANNOUNCED TODAY. Glaxo Wellcome announced today (9/21) that the amprenavir expanded access program is starting for both adults and children (,4 yrs). You or your doctor can call-. 1-800-248-9757 immediately to receive information about enrollment. You or your doctor can call to give the company your doctors name and address. On Sept 28 they will send out expanded access program binders explaining the program. As soon as a person is enrolled in the program drug will be sent out. The company is submitting their NDA to the FDA for accelerated approval in October. Review and approval can take usually from 3-6 months, meaning approval will not come sooner than January 1999.. The program is uniquely offering 3 options for accessing amprenair-. 1. Individuals experiencing adverse side effects from their current PI regimen such as lipodystrophy or elevated lipids but are not failing their current PI regimen can enroll in this option. The purpose is to try and collect ...
BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. PATIENTS AND METHODS: A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). RESULTS: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% ...
As part of a plan to focus its research activities on fewer therapeutic areas, AstraZeneca is shutting down its Avishkar R&D site in Bangalore, India. The closure will cost 168 jobs in pharmaceutical development and drug discovery for neglected tropical diseases, tuberculosis, and malaria, all areas AstraZeneca will not pursue further. Work will continue on AZD5847, in Phase II studies for tuberculosis, and AstraZeneca will still make available its compound library to open-innovation partners.. ...
Emergency Use Listing granted to AstraZeneca and Serum Institute of India enabling global access to the vaccine. AstraZenecas COVID-19 vaccine has been granted Emergency Use Listing (EUL) by the World Health Organization (WHO) for active immunisation to prevent COVID-19 in individuals 18 years of age and older, including those over 65.. The authorisation of COVID-19 Vaccine AstraZeneca manufactured by AstraZeneca, and COVISHIELD manufactured by Serum Institute of India (SII), enables global access to the vaccine during the pandemic.. The EUL allows for two doses of the vaccine to be administered at a four to 12-week interval. This regimen was shown in clinical trials to be safe and effective in preventing symptomatic COVID-19, with no severe cases and no hospitalisations more than 14 days after the second dose. The WHOs Strategic Advisory Group of Experts on Immunization (SAGE) recommended a dosing interval of eight to 12 weeks. In addition, they also recommended use of the vaccine in ...
Disclosure of Interest D. Pappas Employee of: CORRONA, Inc., Paid instructor for: Novartis, K. Lampl Shareholder of: AstraZeneca, Employee of: AstraZeneca, J. Kremer Shareholder of: CORRONA, Inc., Employee of: CORRONA, Inc., S. Radominski Grant/research support: Pfizer,BMS,AstraZeneca, Amgen, Sanofi, Novartis, Celltrion, Roche;, Consultant for: Pfizer,BMS,AstraZeneca, Employee of: Universidade Federal do Parana- Curitiba- Brzazil;, Speakers bureau: Pfizer,BMS,AstraZeneca,Janssen,Sanofi, GSK, J. Gal: None declared, F. Nyberg Shareholder of: AstraZeneca, Employee of: AstraZeneca, A. Malaviya Consultant for: Part-time Consultant Rheumatologist at ISIC Hospital, Advisory Board Member Janssen Pharma, Roche Pharma, Pfizer Pharma, Sanofi Pharma, A. Whitworth Employee of: CORRONA, Inc., O. Rillo: None declared, A. Gibofsky Shareholder of: Amgen, BMS, GlaxoSmithKline, Johnson & Johnson, Pfizer, Roche, Consultant for: Amgen, AstraZeneca, Celgene, Horizon, Iroko, Pfizer, Roche, Antares, UCB, Speakers ...
Astrazeneca News Headlines. AZN Share News. Financial News Articles for Astrazeneca Plc Ord Shs $0.25 updated throughout the day.
At present, the third generation of platinum-based regimens (NCCN clinical practice guidelines recommended the use of vinorelbine or gemcitabine, or Taxol, etc.) is the first-line treatment for advanced lung cancer patients. Its effective rate is 20-30%, the median survival time is 7-9 months, 1-year and 2-year survival rate is 31-36% and 10-13% respectively. The efficacy has reached the platform and it is difficult to have more breakthroughs. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as Iressa and Erlotinib have proved effective in first or second line therapy for advanced non-small cell lung cancer(NSCLC).First-SIGNAL and IPASS research have laid first-line status for gefitinib in treatment of NSCLC and the progression-free survival time was maintained at 9-10 months. EGFR-TKIs treatment is simple, well tolerated, drug side effects, etc. There are also a rash, diarrhea and other adverse reactions, affecting the quality of life of patients with serious or even ...
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) will be the 1st\line treatment for individuals with mutant non\little\cell lung cancer (NSCLC). in the osimertinib group (= 41) vs the platinum\pemetrexed group (= 22; risk percentage 0.27; 95% self-confidence period, 0.13\0.56). The median PFS was 12.5 and 4.three months in the osimertinib and platinum\pemetrexed groups, respectively. Quality 3 adverse MK-5172 hydrate IC50 occasions determined to become linked to treatment happened in 5 individuals (12.2%) treated with osimertinib and 12 individuals (54.5%) treated with platinum\pemetrexed. The security and effectiveness leads to this subanalysis are in keeping with the outcomes of the entire AURA3 research, and support the usage of osimertinib in Japanese individuals with T790M mutation\positive NSCLC whose disease offers progressed following 1st\collection EGFR\TKI treatment. (ClinicalTrials.gov trial sign up zero. NCT02151981.) gene resulting in T790M is situated in ...
Zeinyeh W, Esvan YJ, Josselin B, Baratte B, Bach S, Nauton L, Théry V, Ruchaud S, Anizon F, Giraud F, Moreau P. Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis, SAR and molecular modeling studies. Bioorg Med Chem. 2019 May 15;27(10):2083-2089. doi: 10.1016/j.bmc.2019.04.005.. Chassé H., Boulben S., Glippa V., Pontheaux F., Cormier P., Morales J. (2019) In vivo analysis of protein translation activity in sea urchin eggs and embryos. Methods in Cell Biol Vol. 151, doi: 10.1016/bs.mcb.2018.10.008. Falaise C, Cormier P, Tremblay R, Audet C, Deschênes JS, Turcotte F, François C, Seger A, Hallegraeff G, Lindquist N, Sirjacobs D, Gobert S, Lejeune P, Demoulin V, Mouget JL. (2019) Harmful or harmless: Biological effects of marennine on marine organisms. Aquat Toxicol. 209:13-25. doi: 10.1016/j.aquatox.2019.01.016.. Chassé H., Boulben S., Cormier P., Morales J. (2019) Translational control of canonical and non-canonical translation initiation factors at the sea urchin egg to ...
ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986.[7][8][9][10] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.[8] Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing.[7][11] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.[12]. Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.[13][14] In 2007 a ROS1 rearrangement was identified in a cell line ...
RNS Number: 0958 T AstraZeneca PLC 18 March 2019 18 March 2019 07:00 GMT. US FDA grants saracatinib Orphan Drug Designation. The US Food and Drug...
OncoLink, the Webs first cancer resource,provides comprehensive information on coping with cancer, cancer treatments, cancer research advances, continuing medical education, cancer prevention, and clinical trials
Referenzen: 1. Schill C et al. Nicht-kleinzelliges Bronchialkarzinom. Schweiz Med Forum. 2015;15(19):453- 458. 2. Sharma SV et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169-81.. 3. Wells A et al. EGF receptor. Int J Biochem Cell Biol. 1999;31:637 -643.. 4. Wakeling A et al. ZD1839 (Iressa): An Orally Active Inhibitor of Epidermal Growth Factor Signaling with Potential for Cancer Therapy. Cancer Res. 2002;62(20):5749-54.. 5. Tapia C et al. EGFR-Mutationsanalyse beim nichtkleinzelligen Lungenkarzinom: Erfahrungen aus der Routinediagnostik. Pathologe 2009;30(5):384-392. 6. Sekine I et al. Emerging ethnic differences in lung cancer therapy. Br J Cancer. 2008;99:1757-1762.. 7. Lynch TJ et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129 -2139.. 8. Fachinformation Schweiz IRESSA® (www.swissmedicinfo.ch), M-Files Approval: 13213 (last ...
Amgen and AstraZeneca announce positive results from Phase III study of brodalumab (AMG 827) in patients with moderate-to-severe plaque psoriasis
George J. Cerniglia, Nabendu Pore, Jeff H. Tsai, Susan Schultz, Rosemarie Mick, Regine Choe, Xiaoman Xing, Turgut Durduran, Arjun G. Yodh, Sydney M. Evans, Cameron J. Koch, Stephen M. Hahn, Harry Quon, Chandra M. Sehgal, William M.F. Lee, Amit Maity ...
Currently, there is no standard salvage regimen after the failure of cisplatin-based chemotherapy for advanced urothelial carcinoma. Many novel agents have been developed and have shown modest activity in urothelial carcinoma. With the advancement of molecular biology and a deeper understanding of the pathogenesis of urothelial carcinoma, new approaches for treating patients using molecularly targeted therapies have emerged. Previous studies have shown that the over-expression of epidermal growth factor receptor (EGFR) predicts poor survival and stage progression [4, 5]. EGFR is more strongly expressed in invasive tumors (pT2-T4) and high-grade tumors than in superficial or low-grade tumors [4]. However, mutations within the kinase domain and truncations of the EGFR are rarely seen in bladder cancer, and they have emerged as attractive therapeutic targets. Cetuximab (an EGFR inhibitor) is a chimeric human/mouse monoclonal antibody that prevents dimerization by binding to the extracellular domain ...
Array Receives $1,000,000 Milestone Payment from AstraZeneca -. BOULDER, Colo., Jan. 24 /PRNewswire-FirstCall/ -- Array BioPharma Inc. (Nasdaq: ARRY) and AstraZeneca PLC selected an additional clinical candidate for their small molecule anti-cancer program, triggering a $1 million milestone payment from AstraZeneca to Array. In December 2003, Array partnered the oncology portion of its MEK program, including its lead compound, ARRY-142886 (AZD6244), for co-development and commercialization with AstraZeneca. At that time, Array and AstraZeneca established a collaboration for research and development of additional clinical candidates.. We are pleased that our collaboration with AstraZeneca has yielded an additional high quality development candidate, said Kevin Koch, Ph.D., President and Chief Scientific Officer, Array BioPharma. Our first proprietary compound, ARRY-142886, continues to make good progress in Phase Ib. We believe the data generated in this study will support more advanced ...
The AstraZeneca vaccine prompts cells to make a specific part of SARS-CoV-2 (the virus that causes COVID-19), called the spike protein, which the virus uses to attach to cells when infecting us.. The vaccine stimulates our immune system to generate antibodies against the spike protein, which then primes the body to mount an immune response against SARS-CoV-2, if it encounters the virus in the future.. But in some people, the AstraZeneca vaccine seems to produce antibodies that react with platelets, making them stick together, leading the blood to clot. This in turn reduces circulating platelet numbers, and hence the thrombocytopenia.. These antibodies are similar to those found in some people on a blood thinning drug called heparin. The immune response to heparin generates antibodies that bind to platelets. This can lead to blood clots in some people, called heparin induced thrombocytopenia. As many as one in 20 patients receiving heparin develop thrombocytopenia.. Keeping in mind were yet to ...
Using CO LOSARTAN TAB 100MG during pregnancy may raise the risk of children developing some disorder (commpon for some such kind of drugs), however it depends upon how CO LOSARTAN TAB 100MG ingredients pass through placenta and may have effect on baby - Strength of CO LOSARTAN TAB 100MG is major factor in determination of such side effects, The possible danger in pregnancy are under research. ASTRAZENECA FARMACEUTICA SPAIN, S.A Canada publish leaflet about CO LOSARTAN TAB 100MG every update to describe possible risks of using CO LOSARTAN TAB 100MG side effect in pregnancy and pregnant women. You may download ASTRAZENECA FARMACEUTICA SPAIN, S.A issued leaflet regarding side effects of CO LOSARTAN TAB 100MG - LOSARTAN POTASSIUM. Pregnancy Side Effects can be easily know by Atc code of CO LOSARTAN TAB 100MG ATC CODE.. ...
The Oxford / AstraZeneca vaccine does not use the revolutionary genetic technology of mRNA or messenger RNA like Pfizer and Moderna, but the more traditional virus-vector type that takes as a carrier another virus (a chimpanzee adenovirus) although genetically modified and adapted to combat Covid-19.. However, it has been criticized due to the confusion in the interim results of clinical trials. The British laboratory announced in November that its vaccine had an average efficacy of 70%, compared to more than 90% for the Pfizer / BioNTech and Moderna vaccines.. The efficacy of the AstraZeneca / Oxford vaccine was 90% for volunteers who received a half dose first and then a full dose one month later, but only 62% for another group that was more frequently vaccinated with two full doses with a month difference.. The half-dose injection was, in fact, due to an error and only a small group had followed the second protocol, which had raised concern, and led the company to announce on November 26 ...
The Food and Drug Administration (FDA) has asked hospitals and pharmacies to recall batches of rosuvastatin - a drug to control cholesterol marketed as Crestor - which the agency said had been mixed with counterfeit drugs. FDA official Chih Lan-hui (遲蘭慧) said that global biopharmaceutical company AstraZeneca received a report from a pharmacist in New Taipei City last month that its Crestor 10mg film-coated tablets might contain counterfeit drugs in similar packaging. The company confirmed the product was fake after sending a sample abroad to be examined. The FDA received the report from AstraZeneca on Thursday and the New Taipei District Prosecutors Office
FDA Approves AstraZeneca PLC (AZN)s Seroquel(R) for Maintenance Treatment in Bipolar Disorder WILMINGTON, Del., May 14 /PRNewswire-FirstCall/ -- AstraZeneca (NYSE: AZN - News) today announced that
Both pieces of news will be welcomed by Chief Executive Pascal Soriot, who is determined to prove AstraZeneca has a strong independent future after fending off Pfizer. Many analysts believe Pfizer could repeat its bid to buy AstraZeneca later this year.. EASTERN EUROPEAN PATIENTS. The results of the so-called PLATO study into Brilinta were first reported at a medical meeting in 2009 and went on to form the basis of successful new drug applications in the United States, Europe and other markets. Brilinta was launched in 2011. [eap_ad_2] But various aspects of the study, which relied heavily on patients recruited in eastern Europe, have been criticized over the years by a number of medical experts. Poland and Hungary together accounted for 21 percent of all subjects studied - more than double the United States and Canada combined.. Two doctors, James DiNicolantonio of Ithaca, New York and Ales Tomek of Charles University in Prague, raised several questions about the conduct of the study in a paper ...
Last year, the FDA called for stronger heart-failure warnings on the label of AstraZeneca Type 2 diabetes med Onglyza. And now, AstraZeneca and former partner Bristol-Myers Squibb are being hit with 14 lawsuits related to the meds heart-failure risks.
The more than two million Canadians who received the AstraZeneca-Oxford COVID-19 vaccine made the right choice and should not regret their decision, health experts say, despite the fact that some provinces are pausing rollout of the vaccine over concerns about the risk of rare blood clots. In fact, Dr. David Naylor, co-chair of the national COVID-19 Immunity Task Force, thanked those who received the AstraZeneca vaccine, saying their actions protected them and others around them. He noted that when AstraZeneca first came into use, several provinces were in the grips of an intensifying third wave of COVID-19. The risks were obvious, with scores of Canadians dying every week and many more hospitalized, including those with illness severe enough to require intensive care and mechanical ventilation, he said in an email. It made very good sense in those circumstances to follow public health advice about taking the first vaccine on offer. Dr. Zain Chagla, an infectious diseases physician at St. Josephs
Nexium esomeprazole 40 mg astrazeneca, nexium drip indication, nexium 40mg price uk, what is nexium 24hr, astrazeneca nexium news, nexium versus prilosec otc, help buying nexium
Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations. Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry. Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%