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Rahul Dwivedi, Sambath Tiroumal
PURPOSE: Paclitaxel (Taxol) is a microtubule-stabilizing agent and belongs to the taxane group of chemotherapeutic drugs. It is used to treat numerous malignancies, such as breast and lung cancers. A rare side effect of this drug includes cystoid macular edema (CME), which is presumed to resolve after cessation of Paclitaxel. We present a case of topical Dorzolamide 2% (Trusopt) having a possible successful effect in the treatment of Paclitaxel-related nonresolving CME. By highlighting this rare ocular side effect of a common chemotherapeutic agent, which fails to resolve upon cessation of the drug alone, we suggest a possible treatment that may help other ophthalmologists in their management of similar cases...
October 4, 2016: Retinal Cases & Brief Reports
August Cesarec, Robert Likić
BACKGROUND AND OBJECTIVE: Breast cancer is the most common cancer in women and has considerable impact on healthcare budgets and patients' quality of life. Trastuzumab (Herceptin(®)) is a monoclonal antibody directed against the human epidermal growth factor receptor (HER2) for the treatment of breast cancer. Several trastuzumab biosimilars are currently in development. In 2015, trastuzumab was the drug with the highest financial consumption among all drugs in Croatia. This model estimates the 1-year budget impact of the introduction of biosimilar trastuzumab in Croatia...
October 11, 2016: Applied Health Economics and Health Policy
Huiping Shi, Weili Zhang, Qiaoming Zhi, Min Jiang
In the era of new and mostly effective molecular targeted therapies, human epidermal growth factor receptor 2 positive (HER2+) cancers are still intractable diseases. Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor, has greatly improved breast cancer prognosis in recent years after the initial introduction of trastuzumab (Herceptin). However, clinical evidence indicates the existence of both primary unresponsiveness and secondary lapatinib resistance, which leads to the failure of this agent in HER2+ cancer patients...
October 10, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
T Yu, G Yang, Y Hou, X Tang, C Wu, X-A Wu, L Guo, Q Zhu, H Luo, Y-E Du, S Wen, L Xu, J Yin, G Tu, M Liu
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs...
October 10, 2016: Oncogene
Balazs T Nemeth, Zoltan V Varga, Wen Jin Wu, Pal Pacher
Epidermal growth factor receptor-2 (HER-2) is overexpressed in 20% to 25% of human breast cancers, which is associated with aggressive tumor growth and poor prognosis. Trastuzumab (Herceptin®) is a humanized monoclonal antibody directed against HER-2, the first highly selective form of therapy targeting HER-2 overexpressing tumors. Although initial trials indicated high efficacy and a favorable safety profile of the drug, the first large, randomized trial prompted a retrospective analysis of cardiac dysfunction in prior trials utilizing trastuzumab...
October 7, 2016: British Journal of Pharmacology
Feng Tang, Yang Yang, Yubo Tang, Shuai Tang, Liyun Yang, Bingyang Sun, Bofeng Jiang, Jinhua Dong, Hong Liu, Min Huang, Mei-Yu Geng, Wei Huang
Chemoenzymatic transglycosylation catalyzed by endo-S mutants is a powerful tool for in vitro glycoengineering of therapeutic antibodies. In this paper, we report a one-pot chemoenzymatic synthesis of glycoengineered Herceptin using an egg-yolk sialylglycopeptide (SGP) substrate. Combining this one-pot strategy with novel non-natural SGP derivatives carrying azido or alkyne tags, glycosite-specific conjugation was enabled for the development of new antibody-drug conjugates (ADCs). The site-specific ADCs and semi-site-specific dual-drug ADCs were successfully achieved and characterized with SDS-PAGE, intact antibody or ADC mass spectrometry analysis, and PNGase-F digestion analysis...
October 12, 2016: Organic & Biomolecular Chemistry
Yan Liu, Ying Wang, Yong Zhang, Tao Liu, Haiqun Jia, Huafei Zou, Qiangwei Fu, Yuhan Zhang, Lucy Lu, Elizabeth Chao, Holly Parker, Van Nguyen-Tran, Weijun Shen, Danling Wang, Peter G Schultz, Feng Wang
Recent studies have suggested that modulation of two or more signaling pathways can achieve substantial weight loss and glycemic stability. We have developed an approach to the generation of bifunctional antibody agonists that activate leptin receptor and GLP-1 receptor. Leptin was fused into the complementarity determining region 3 loop of the light chain alone, or in combination with exendin-4 (EX4) fused at the N-terminus of the heavy chain of Herceptin. The antibody fusions exhibit similar or increased in vitro activities on their cognate receptors, but 50-100-fold longer circulating half-lives in rodents compared to the corresponding native peptides/proteins...
October 5, 2016: ACS Chemical Biology
Jin-Ki Noh, Muhammad Naeem, Jiafu Cao, Eun Hee Lee, Min-Soo Kim, Yunjin Jung, Jin-Wook Yoo
The objective of this study was to prepare Herceptin (HCT)-functionalized paclitaxel nanocrystals and evaluated their cell-specific interactions, cellular accumulation, and growth inhibition in HER2-positve breast cancer cells as a tumor-targeted delivery module. Paclitaxel (PTX) was fabricated in the form of nanocrystals (PNCs) by a sono-precipitation method, and HCT were coated using a facile non-covalent method (PNCs-HCT). Our results showed that the PNCs-HCT were stable for at least 1month at 4°C with no noticeable desorption of HCT...
September 26, 2016: International Journal of Pharmaceutics
S Lefort, A Thuleau, Y Kieffer, P Sirven, I Bieche, E Marangoni, A Vincent-Salomon, F Mechta-Grigoriou
The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties...
September 26, 2016: Oncogene
H Kim, S N Danishmalik, H Hwang, J-I Sin, J Oh, Y Cho, H Lee, M Jeong, S-H Kim, H J Hong
Plasmid DNA-encoded antibodies, or DNA-based monoclonal antibodies (dMAbs), are delivered by intramuscular injection and in vivo electroporation (EP) and are effective in virus neutralization, although they have not been evaluated for tumor gene therapy. Here we investigated whether a dMAb was appropriate for tumor gene therapy. We constructed the expression plasmids coding for the heavy or light chain of a parental murine antibody of Herceptin with the antibody genes codon- and RNA-optimized and fused to the Kozak-IgE leader sequence in pVax1...
September 16, 2016: Cancer Gene Therapy
A King, J Thambyrajah, E Leng, M J Stewart
Herceptin (Trastuzumab) is a widely used and effective drug for the treatment of Her2+ breast cancer but its cardiotoxic side effects require regular monitoring by echocardiography. A 10% reduction in left ventricular ejection fraction can lead to suspension of treatment and therefore has significant implications for patient prognosis in terms of cardiac and cancer outcomes. Assessment of LV function by conventional 2D biplane method of discs (2DEF) has limitations in accuracy and reproducibility. Global longitudinal strain (GLS) is becoming more widely available and user friendly...
September 2016: Echo Research and Practice
Rosie Upton, Leonard Bell, Colin Guy, Paul Caldwell, Sian Estdale, Perdita E Barran, David Firth
In the development of therapeutic antibodies and biosimilars, an appropriate biopharmaceutical CMC control strategy that connects critical quality attributes with mechanism of action should enable product assessment at an early stage of development in order to mitigate risk. Here we demonstrate a new analytical workflow using trastuzumab which comprises "middle-up" analysis using a combination of IdeS and the endoglycosidases EndoS and EndoS2 to comprehensively map the glycan content. Enzymatic cleavage between the two N-acetyl glucosamine residues of the chitobiose core of N-glycans significantly simplifies the oligosaccharide component enabling facile distinction of GlcNAc from GlcNAc with core fucose...
October 18, 2016: Analytical Chemistry
Yanxun Xu, Lorenzo Trippa, Peter Müller, Yuan Ji
Targeted therapies based on biomarker profiling are becoming a mainstream direction of cancer research and treatment. Depending on the expression of specific prognostic biomarkers, targeted therapies assign different cancer drugs to subgroups of patients even if they are diagnosed with the same type of cancer by traditional means, such as tumor location. For example, Herceptin is only indicated for the subgroup of patients with HER2+ breast cancer, but not other types of breast cancer. However, subgroups like HER2+ breast cancer with effective targeted therapies are rare and most cancer drugs are still being applied to large patient populations that include many patients who might not respond or benefit...
June 2016: Statistics in Biosciences
Thomas B Parsons, Weston B Struwe, Joseph Gault, Keisuke Yamamoto, Thomas A Taylor, Ritu Raj, Kim Wals, Shabaz Mohammed, Carol V Robinson, Justin L P Benesch, Benjamin G Davis
Glycosylation patterns in antibodies critically determine biological and physical properties but their precise control is a significant challenge in biology and biotechnology. We describe herein the optimization of an endoglycosidase-catalyzed glycosylation of the best-selling biotherapeutic Herceptin, an anti-HER2 antibody. Precise MS analysis of the intact four-chain Ab heteromultimer reveals nonspecific, non-enzymatic reactions (glycation), which are not detected under standard denaturing conditions. This competing reaction, which has hitherto been underestimated as a source of side products, can now be minimized...
February 12, 2016: Angewandte Chemie
Emma L Wilkinson, James E Sidaway, Michael J Cross
Cardiotoxicity induced by anti-cancer therapeutics is a severe, and potentially fatal, adverse reaction of the heart in response to certain drugs. Current in vitro approaches to assess cardiotoxicity have focused on analysing cardiomyocytes. More recently it has become apparent that non-cardiomyocyte cells of the heart can potentially contribute to cardiotoxicity. Herceptin and doxorubicin are known to induce cardiotoxicity in the clinic. The effect of these drugs on the endothelial tight junction barrier was tested by analysing tight junction formation and zona occludens-1 (ZO-1) levels, revealing that Herceptin and doxorubicin are able to induce barrier perturbment and decrease barrier function in human cardiac microvascular endothelial cells (HCMECs) leading to increased permeability...
October 15, 2016: Biology Open
Jonathan Walter Esclovon, Melissa Ponder, Nail Aydin, Subhasis Misra
A 59-year-old woman with right breast mass was diagnosed with invasive ductal carcinoma (IDC). Workup consisted of bilateral diagnostic mammogram and ultrasound (US); both showed a right breast mass with normal left breast. Core biopsy showed IDC with estrogen receptor negative (ER-)/progesterone receptor negative (PR-) and HER2/neu positive receptor status. The patient underwent carboplatin-based chemotherapy with Herceptin. The mass completely resolved. The patient desired to proceed with bilateral total mastectomy with right sentinel lymph node biopsy (SLNB)...
August 18, 2016: BMJ Case Reports
Wang Ding, Kailash Chandra Gupta, Soo-Young Park, Young-Kyoo Kim, Inn-Kyu Kang
The present study utilizes antibody-protein interactions to develop an LC microdroplet based biosensor for naked eye detection of SK-BR3 human breast cancer cells. The herceptin antibody-conjugated LC microdroplets were fabricated using 4-cyano-4'-pentyl biphenyl (5CB) as the liquid crystalline phase and sodium dodecyl sulfate (SDS) as the surfactant. The poly (styrene-b-acrylic acid) amphiphilic block copolymer (PS-b-PA) played a role as a modifier for the liquid crystalline interfaces. The 5CB molecules in the herceptin antibody-conjugated LC microdroplets have shown an orientation transition from radial to bipolar on selective interactions with targeted SK-BR3 breast cancer cells, which are over expressed by the human epidermal growth factor receptor 2-positive (HER2)...
October 20, 2016: Biomaterials Science
Thomas Marcuzzo, Fabiola Giudici, Elisa Ober, Clara Rizzardi, Cristina Bottin, Fabrizio Zanconati
AIM: Her2 protein is the key marker determining the choice of Herceptin therapy after a diagnosis of breast cancer. Its evaluation is made in most laboratories by immunohistochemistry, and interpreted by a pathologist using an optical microscope, a process subject to inter-observer variability, particularly for samples scored as equivocal (2+). Software analysis products have been introduced, seeking to reduce this variability. In this study, we compared the results of both traditional evaluation and a specific software package (VISIA Imaging) to those from fluorescent in situ hybridization (FISH)...
August 2, 2016: Pathology, Research and Practice
Kongtong Yu, Yulin Zhou, Yuhuan Li, Xiangshi Sun, Fengying Sun, Xinmei Wang, Hongyan Mu, Jie Li, Xiaoyue Liu, Lesheng Teng, Youxin Li
Research on quantitatively controlling the ligand density on the surface of nanocarriers is in the frontier and becomes a technical difficulty for targeted delivery system designing. In this study, we developed an improved pre-conjugation (Imp) strategy, in which herceptin as a ligand was pre-conjugated with DSPE-PEG2000-Mal via chemical cross-linking, followed by conjugation onto the surface of pre-prepared paclitaxel-loaded PLGA/DODMA nanoparticles (PDNs) through hydrophobic interaction and electrostatic attraction for paclitaxel delivery...
August 19, 2016: Biomaterials Science
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