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Sandeep Pallerla, Ted Gauthier, Rushikesh Sable, Seetharama D Jois
Doxorubicin (DOX) belongs to the anthracycline class of drugs that are used in the treatment of various cancers. It has limited cystostatic effects in therapeutic doses, but higher doses can cause cardiotoxicity. In the current approach, we conjugated a peptidomimetic (Arg-aminonaphthylpropionic acid-Phe, compound 5) known to bind to HER2 protein to DOX via a glutaric anhydride linker. Antiproliferative assays suggest that the DOX-peptidomimetic conjugate has activity in the lower micromolar range. The conjugate exhibited higher toxicity in HER2-overexpressed cells than in MCF-7 and MCF-10A cells that do not overexpress HER2 protein...
October 10, 2016: European Journal of Medicinal Chemistry
Henrik Hasle, Gertjan J L Kaspers
Over the last four decades the survival of paediatric patients with acute myeloid leukaemia has gradually increased to 70% in high-income countries. The therapy is very intensive and associated with many acute and long-term side effects. The early death rate has been reduced to 1-4%. The acute toxicity is a limiting factor for improving survival in low-income countries. Transplant is associated with more endocrinological late effects while cardiotoxicity is more common after relapse. Reducing the physical costs of therapy without jeopardizing survival may be accomplished by optimal supportive care, less cardiotoxic anthracyclines, less consolidation courses and strict indications for stem cell transplantation...
October 21, 2016: British Journal of Haematology
Hui Yao, Guangchun He, Shichao Yan, Chao Chen, Liujiang Song, Thomas J Rosol, Xiyun Deng
Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors...
September 27, 2016: Oncotarget
J Panek, E Koziolova, P Stepanek, T Etrych, O Janouskova
Nanocarriers bearing anticancer drugs are promising candidates to improve the efficacy of cancer therapy and minimize side effects. The most potent cytostatics used in the treatment of various cancers are anthracyclines, e.g. doxorubicin or pirarubicin. Recently, polymer therapeutics carrying anthracyclines have been intensively studied. The precise characterization of in vitro nanocarrier biological behavior brings a better understanding of the nanocarrier characteristics and enables prediction of the behavior of the nanocarrier during in vivo application...
October 20, 2016: Physiological Research
Saverio Cinieri, Arlene Chan, Kadri Altundag, An Vandebroek, Nicole Tubiana-Mathieu, Agusti Barnadas, Patricia Dodyk, Silvia Lazzarelli, Michiel Botha, Daniel Rauch, Gustavo Villanova, Ugur Coskun
BACKGROUND: The purpose of this study was to evaluate the efficacy of 3 first-line chemotherapy combination regimens for HER2-negative metastatic breast cancer (mBC). PATIENTS AND METHODS: In this open-label, 3-arm, randomized phase II trial, patients were randomized to all-oral NORCAP (vinorelbine/capecitabine), GEMPAC (gemcitabine/paclitaxel), or GEMDOC (gemcitabine/docetaxel) as first-line chemotherapy for HER2-negative mBC. Stratification factors were center, previous (neo)adjuvant anthracycline, and age...
June 25, 2016: Clinical Breast Cancer
Paolo Spallarossa, Nicola Maurea, Christian Cadeddu, Rosalinda Madonna, Donato Mele, Ines Monte, Giuseppina Novo, Pasquale Pagliaro, Alessia Pepe, Carlo G Tocchetti, Concetta Zito, Giuseppe Mercuro
Anthracyclines are the mainstay of treatment of a variety of haematological malignancies and solid tumours. Unfortunately, the clinical use of these drugs is limited by cumulative, dose-related cardiotoxicity which may ultimately lead to a severe and irreversible form of cardiomyopathy. Thus, there is an increasing need for close cooperation among cardiologists, oncologists and haemato-oncologists. As anthracyclines save lives, the logical goal of this cooperation, besides preventing or mitigating cardiotoxicity, is to promote an acceptable balance between the potential cardiac side effects and the vital benefit of anticancer treatment...
May 2016: Journal of Cardiovascular Medicine
Martino Deidda, Rosalinda Madonna, Ruggiero Mango, Pasquale Pagliaro, Pier P Bassareo, Lucia Cugusi, Silvio Romano, Maria Penco, Francesco Romeo, Giuseppe Mercuro
Despite advances in supportive and protective therapy for myocardial function, heart failure caused by various clinical conditions, including cardiomyopathy due to antineoplastic therapy, remains a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators have been searching for alternative treatments that can effectively repair the damaged heart and permanently restore its function. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as trastuzumab...
May 2016: Journal of Cardiovascular Medicine
Christian Cadeddu, Valentina Mercurio, Paolo Spallarossa, Savina Nodari, Marco Triggiani, Ines Monte, Roberta Piras, Rosalinda Madonna, Pasquale Pagliaro, Carlo G Tocchetti, Giuseppe Mercuro
Because of the recent advances in chemotherapeutic protocols, cancer survival has improved significantly, although cardiovascular disease has become a major cause of morbidity and mortality among cancer survivors: in addition to the well-known cardiotoxicity (CTX) from anthracyclines, biologic drugs that target molecules that are active in cancer biology also interfere with cardiovascular homeostasis.Pharmacological and non-pharmacological strategies to protect the cardiovascular structure and function are the best approaches to reducing the prevalence of cardiomyopathy linked to anticancer drugs...
May 2016: Journal of Cardiovascular Medicine
Pier P Bassareo, Ines Monte, Claudia Romano, Martino Deidda, Alessandra Piras, Lucia Cugusi, Carmela Coppola, Francesca Galletta, Giuseppe Mercuro
Notwithstanding the steady progress in survival rates of children and adolescents suffering from cancer, the benefits associated with chemotherapy do not come without risks involving multiple organs and systems, including the cardiovascular apparatus. Anthracyclines-often administered in combination with radiation therapy and/or surgery-are the most used chemotherapeutic compounds in order to treat tumours and blood malignancies even in paediatric age. Being an important side-effect of anthracyclines, carduitoxicity may limit their efficacy during the treatment and induce long-term sequelae, observed even many years after therapy completion...
May 2016: Journal of Cardiovascular Medicine
Clelia Madeddu, Martino Deidda, Alessandra Piras, Christian Cadeddu, Laura Demurtas, Marco Puzzoni, Giovanna Piscopo, Mario Scartozzi, Giuseppe Mercuro
The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes)...
May 2016: Journal of Cardiovascular Medicine
Donato Mele, Carlo G Tocchetti, Pasquale Pagliaro, Rosalinda Madonna, Giuseppina Novo, Alessia Pepe, Concetta Zito, Nicola Maurea, Paolo Spallarossa
Anthracyclines (ANTs) are powerful drugs that have reduced the mortality of cancer patients. However, their use is limited by the development of cardiotoxicity (CTX), which is dose dependent and may lead to left ventricular dysfunction and heart failure. Although various strategies have been suggested to reduce the negative effects of ANTs, CTX is still an important unresolved clinical issue. This may be due at least partly to the incomplete characterization of the molecular and cellular mechanisms of ANT-induced CTX...
May 2016: Journal of Cardiovascular Medicine
Mirela Enache, Ana Maria Toader, Madalin Iancu Enache
Mitoxantrone is a synthetic anticancer drug used clinically in the treatment of different types of cancer. It was developed as a doxorubicin analogue in a program to find drugs with improved antitumor activity and decreased cardiotoxicity compared with the anthracyclines. As the cell membrane is the first barrier encountered by anticancer drugs before reaching the DNA sites inside the cells and as surfactant micelles are known as simple model systems for biological membranes, the drugs-surfactant interaction has been the subject of great research interest...
October 13, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Iben Kümler, Eva Balslev, Ann S Knop, Nils Brünner, Tobias W Klausen, Sofie S Jespersen, Signe L Nielsen, Dorte L Nielsen
Tumor heterogeneity has been shown for several cancers including breast cancer (BC). Despite the fact that expression of tumor markers may change throughout the metastatic process, rebiopsies at the time of recurrence are still not performed routinely at all institutions. The aims of the study were to evaluate changes in biomarker profiles during the metastatic process and to investigate whether previous anthracycline or endocrine therapy given in the adjuvant setting could affect the biomarker profile in metastatic lesions...
October 7, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
Olivier Mir, Thomas Brodowicz, Antoine Italiano, Jennifer Wallet, Jean-Yves Blay, François Bertucci, Christine Chevreau, Sophie Piperno-Neumann, Emmanuelle Bompas, Sébastien Salas, Christophe Perrin, Corinne Delcambre, Bernadette Liegl-Atzwanger, Maud Toulmonde, Sarah Dumont, Isabelle Ray-Coquard, Stéphanie Clisant, Sophie Taieb, Cécile Guillemet, Maria Rios, Olivier Collard, Laurence Bozec, Didier Cupissol, Esma Saada-Bouzid, Christine Lemaignan, Wolfgang Eisterer, Nicolas Isambert, Loïc Chaigneau, Axel Le Cesne, Nicolas Penel
BACKGROUND: Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. METHODS: In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment...
October 14, 2016: Lancet Oncology
Xiaoting Gu, Chunxiao Lu, Dongxu He, Yangfan Lu, Jian Jin, Dequan Liu, Xin Ma
To define the role of the NOTCH signaling pathway in the development of chemoresistance and the associated epithelial-mesenchymal transition (EMT), we investigated the effect of Notch3 on adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM cells). We found that Notch3 was downregulated and involved in the chemoresistance of MCF-7/ADM cells, while forced expression of Notch3 reversed the chemoresistance. Furthermore, fos-related antigen 1 (Fra1) was negatively regulated by Notch3 and was highly expressed in MCF-7/ADM cells...
October 14, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Marianne Jarfelt, Niels H Andersen, Henrik Hasle
Since cardiotoxicity is a life threatening late effect, a reduction of cardiotoxicity in the treatment of acute myeloid leukaemia (AML) is essential. This review is a compilation of the current knowledge about cardiotoxicity after AML treatment and of how future directions in treatment may affect its incidence. A total of six studies concerning AML and cardiotoxicity were identified. The incidence of late subclinical cardiotoxicity varied between 1·3 and 15·3%, and late clinical cardiotoxicity varied between 1·3 and 9·3%...
October 14, 2016: British Journal of Haematology
Asish K Ghosh, Rahul Rai, Kitae E Park, Mesut Eren, Toshio Miyata, Lisa D Wilsbacher, Douglas E Vaughan
Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition...
October 6, 2016: Oncotarget
Shyam K Konda, Celine Kelso, Jelena Medan, Brad E Sleebs, Don R Phillips, Suzanne M Cutts, J Grant Collins
The major covalent adduct formed between a (13)C-labelled formaldehyde activated bis-amino mitoxantrone analogue (WEHI-150) and the hexanucleotide d(CG(5Me)CGCG)2 has been isolated by HPLC chromatography and the structure determined by NMR spectroscopy. The results indicate that WEHI-150 forms one covalent bond through a primary amine to the N-2 of the G2 residue, with the polycyclic ring structure intercalated at the (5Me)C3pG4/G10p(5Me)C9 site. Furthermore, the WEHI-150 aromatic ring system is oriented approximately parallel to the long axis of the base pairs, with one aliphatic side-chain in the major groove and the other side-chain in the minor groove...
October 13, 2016: Organic & Biomolecular Chemistry
Yang Yang, Jian-Ge Qiu, Yong Li, Jin-Ming Di, Wen-Ji Zhang, Qi-Wei Jiang, Di-Wei Zheng, Yao Chen, Meng-Ning Wei, Jia-Rong Huang, Kun Wang, Zhi Shi
The RNA-guided clustered regularly interspaced short palindromic (CRISPR) in combination with a CRISPR-associated nuclease 9 (Cas9) nuclease system is a new rapid and precise technology for genome editing. In the present study, we applied the CRISPR/Cas9 system to target ABCB1 (also named MDR1) gene which encodes a 170 kDa transmembrane glycoprotein (P-glycoprotein/P-gp) transporting multiple types of chemotherapeutic drugs including taxanes, epipodophyllotoxins, vinca alkaloids and anthracyclines out of cells to contribute multidrug resistance (MDR) in cancer cells...
2016: American Journal of Translational Research
Mohamad Chehimi, Mathieu Boone, Cyril Chivot, Hervé Deramond, Jean-Marc Constans, Mony Chenda Ly, Bruno Chauffert
There is no effective treatment for recurrent glioblastoma (GB) when temozolomide-based radiochemotherapy fails. In theory, intra-arterial (IA) delivery of cytotoxic agents could achieve higher drug concentrations in tumors compared to intravenous injection. Moreover, choosing a highly lipid-soluble drug could make the most of the first-pass effect. Here, we evaluated idarubicin (IDA), a lipophilic anthracycline, in an in vitro assay using four human GB cell lines and compared it with 11 other drugs previously used for the IA treatment of brain tumors...
May 2016: Case Reports in Oncology
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