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https://www.readbyqxmd.com/read/28641053/the-discovery-and-development-of-romidepsin-for-the-treatment-of-t-cell-lymphoma
#1
Piotr Smolewski, Tadeusz Robak
Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34-35% and 25-38%, with complete response (CR) rates of 6% and 15-18%, respectively...
June 22, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28615266/antitumor-effects-of-epidrug-ifnalpha%C3%A2-combination-driven-by-modulated-gene-signatures-in-both-colorectal-cancer-and-dendritic-cells
#2
Alessandra Fragale, Giulia Romagnoli, Valerio Licursi, Maria Buoncervello, Giorgia Del Vecchio, Caterina Giuliani, Stefania Parlato, Celeste Leone, Marta De Angelis, Irene Canini, Elena Toschi, Filippo Belardelli, Rodolfo Negri, Imerio Capone, Carlo Presutti, Lucia Gabriele
Colorectal cancer (CRC) results from progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRFs) to access regulatory sequences in IFN-stimulated genes (ISGs) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNa2 (ARI) hampers the aggressiveness of both CRC metastatic and stem cells in vivo and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function...
June 14, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28601492/new-agents-in-multiple-myeloma-an%C3%A2-examination-of-safety-profiles
#3
REVIEW
Sara Bringhen, Edwin De Wit, Meletios-Athanassios Dimopoulos
Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib...
May 10, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28566628/histone-deacetylase-inhibitors-sensitize-murine-b16f10-melanoma-cells-to-carbon-ion-irradiation-by-inducing-g1-phase-arrest
#4
Katsuyo Saito, Tomoo Funayama, Yuichiro Yokota, Takashi Murakami, Yasuhiko Kobayashi
Epigenetic processes, in addition to genetic abnormalities, play a critical role in refractory malignant diseases and cause the unresponsiveness to various chemotherapeutic regimens and radiotherapy. Herein we demonstrate that histone deacetylase inhibitors (HDACis) can be used to sensitize malignant melanoma B16F10 cells to carbon ion irradiation. The cells were first treated with HDACis (romidepsin [FK228, depsipeptide], trichostatin A [TSA], valproic acid [VPA], and suberanilohydroxamic acid [SAHA, vorinostat]) and were then exposed to two types of radiation (carbon ions and gamma-rays)...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28560733/complete-remission-with-romidepsin-in-a-patient-with-t-cell-acute-lymphoblastic-leukemia-refractory-to-induction-hyper-cvad
#5
Mark W Brunvand, John Carson
T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are neoplasms that originate from T-cell precursors. Outcomes in adult patients with T-ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T-cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T-cell lymphoma who have had ≥1 prior systemic therapy...
May 30, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28551413/applying-the-chicken-embryo-chorioallantoic-membrane-assay-to-study-treatment-approaches-in-urothelial-carcinoma
#6
Margaretha A Skowron, Anuja Sathe, Andrea Romano, Michèle J Hoffmann, Wolfgang A Schulz, Gommert A van Koeveringe, Peter Albers, Roman Nawroth, Günter Niegisch
BACKGROUND: Rapid development of novel treatment options demands valid preclinical screening models for urothelial carcinoma (UC). The translational value of high-throughput drug testing using 2-dimensional (2D) cultures is limited while for xenograft models handling efforts and costs often become prohibitive for larger-scale drug testing. Therefore, we investigated to which extent the chicken chorioallantoic membrane (CAM) assay might provide an alternative model to study antineoplastic treatment approaches for UC...
May 25, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28529033/high-throughput-characterization-of-hiv-1-reservoir-reactivation-using-a-single-cell-in-droplet-pcr-assay
#7
Robert W Yucha, Kristen S Hobbs, Emily Hanhauser, Louise E Hogan, Wildaliz Nieves, Mehmet O Ozen, Fatih Inci, Vanessa York, Erica A Gibson, Cassandra Thanh, Hadi Shafiee, Rami El Assal, Maja Kiselinova, Yvonne P Robles, Helen Bae, Kaitlyn S Leadabrand, ShuQi Wang, Steven G Deeks, Daniel R Kuritzkes, Utkan Demirci, Timothy J Henrich
Reactivation of latent viral reservoirs is on the forefront of HIV-1 eradication research. However, it is unknown if latency reversing agents (LRAs) increase the level of viral transcription from cells producing HIV RNA or harboring transcriptionally-inactive (latent) infection. We therefore developed a microfluidic single-cell-in-droplet (scd)PCR assay to directly measure the number of CD4(+) T cells that produce unspliced (us)RNA and multiply spliced (ms)RNA following ex vivo latency reversal with either an histone deacetylase inhibitor (romidepsin) or T cell receptor (TCR) stimulation...
May 4, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28506690/romidepsin-induces-caspase-dependent-cell-death-in-human-neuroblastoma-cells
#8
Shane V Hegarty, Katie L Togher, Eimear O'Leary, Franziska Solger, Aideen M Sullivan, Gerard W O'Keeffe
Neuroblastoma is the most common extracranial pediatric solid tumor, arising from the embryonic sympathoadrenal lineage of the neural crest, and is responsible for 15% of childhood cancer deaths. Although survival rates are good for some patients, those children diagnosed with high-risk neuroblastoma have survival rates as low as 35%. Thus, neuroblastoma remains a significant clinical challenge and the development of novel therapeutic strategies is essential. Given that there is widespread epigenetic dysregulation in neuroblastoma, epigenetic pharmacotherapy holds promise as a therapeutic approach...
May 12, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28467787/the-histone-deacetylase-inhibitor-romidepsin-as-a-potential-treatment-for-pulmonary-fibrosis
#9
Franco Conforti, Elizabeth R Davies, Claire J Calderwood, Thomas H Thatcher, Mark G Jones, David E Smart, Sumeet Mahajan, Aiman Alzetani, Tom Havelock, Toby M Maher, Philip L Molyneaux, Andrew J Thorley, Teresa D Tetley, Jane A Warner, Graham Packham, A Ganesan, Paul J Skipp, Benjamin J Marshall, Luca Richeldi, Patricia J Sime, Katherine M A O'Reilly, Donna E Davies
Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials...
April 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28406576/antitumor-activity-and-pharmacologic-characterization-of-the-depsipeptide-analog-as-a-novel-histone-deacetylase-phosphatidylinositol-3-kinase-dual-inhibitor
#10
Ken Saijo, Hiroo Imai, Sonoko Chikamatsu, Koichi Narita, Tadashi Katoh, Chikashi Ishioka
Histone deacetylase (HDAC)/phosphatidylinositol 3-kinase (PI3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an HDAC/PI3K dual inhibitor is reasonably attractive. Romidepsin (FK228, depsipeptide) is a potent HDAC inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as PI3K inhibitors and are defined as HDAC/PI3K dual inhibitors...
April 12, 2017: Cancer Science
https://www.readbyqxmd.com/read/28340883/novel-agents-in-the-treatment-of-relapsed-or-refractory-peripheral-t-cell-lymphoma
#11
REVIEW
Enrica Marchi, Alexander G Raufi, Owen A O'Connor
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature T-cell malignancies associated with exceptionally poor prognoses. Currently, chemotherapy remains the standard of care, but outcomes are suboptimal, with 5-year survival rates ranging from 15% to 25%. In recent years, several novel agents, including pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have been approved for the treatment of relapsed/refractory PTCL. In addition, numerous other therapies with different mechanisms of action and targets are currently under investigation...
April 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28272134/romidepsin-induced-hiv-1-viremia-during-effective-antiretroviral-therapy-contains-identical-viral-sequences-with-few-deleterious-mutations
#12
Anni Winckelmann, Kirston Barton, Bonnie Hiener, Timothy E Schlub, Wei Shao, Thomas A Rasmussen, Lars Østergaard, Ole S Søgaard, Martin Tolstrup, Sarah Palmer
OBJECTIVE: To investigate the origin of the HIV-1 viremia induced by the latency-reversing agent romidepsin. DESIGN: Six individuals on suppressive antiretroviral therapy received romidepsin administered intravenously once weekly for 3 consecutive weeks. CD4 T cells were obtained at baseline, following the second and third romidepsin infusion, and 10 weeks after the final romidepsin treatment. Plasma samples were collected 24 and 72 h after romidepsin infusions...
March 27, 2017: AIDS
https://www.readbyqxmd.com/read/28264616/romidepsin-is-effective-and-well-tolerated-in-older-patients-with-peripheral-t-cell-lymphoma-analysis-of-two-phase-ii-trials
#13
Andrei Shustov, Bertrand Coiffier, Steven Horwitz, Lubomir Sokol, Barbara Pro, Julie Wolfson, Barbara Balser, Robin Eisch, Leslie Popplewell, H Miles Prince, Steven L Allen, Richard Piekarz, Susan Bates
Peripheral T-cell lymphomas (PTCLs) are a rare group of lymphoid neoplasms with high relapse rates after initial therapy and poor prognosis. Most patients are aged ≥60 years and are often not candidates for aggressive salvage therapies. Romidepsin, a potent class I histone deacetylase inhibitor, has shown significant single-agent activity in relapsed/refractory PTCL. We evaluated the efficacy and tolerability of romidepsin in elderly patients in this setting. Ninety-five patients aged ≥60 years were identified from 2 prospective phase 2 registration trials of romidepsin, and comparative analyses were performed with younger patients from these trials...
March 7, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28202759/relationship-between-measures-of-hiv-reactivation-and-decline-of-the-latent-reservoir-under-latency-reversing-agents
#14
Janka Petravic, Thomas A Rasmussen, Sharon R Lewin, Stephen J Kent, Miles P Davenport
Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation...
May 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28181261/the-search-for-potent-small-molecule-hdacis-in-cancer-treatment-a-decade-after-vorinostat
#15
REVIEW
Chiara Zagni, Giuseppe Floresta, Giulia Monciino, Antonio Rescifina
Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade, inhibition of HDACs came out as a target for specific epigenetic changes associated with cancer and other diseases. Until now, more than 20 HDAC inhibitors (HDACIs) have entered clinical studies, and some of them (e.g., vorinostat, romidepsin) have been approved for the treatment of cutaneous T-cell lymphoma. This review provides an overview of current knowledge, progress, and molecular mechanisms of HDACIs, covering a period from 2011 until 2015...
February 9, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28119491/reactive-oxygen-species-mediated-synergism-of-fenretinide-and-romidepsin-in-preclinical-models-of-t-cell-lymphoid-malignancies
#16
Monish R Makena, Balakrishna Koneru, Thinh H Nguyen, Min H Kang, C Patrick Reynolds
T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in fifteen TCLM cell lines at clinically-achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells)...
January 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28115372/peripheral-t-cell-lymphoma-not-otherwise-specified
#17
REVIEW
Alessandro Broccoli, Pier Luigi Zinzani
Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any other of the existing entities defined by the World Health Organization classification. Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), nowadays represent the standard first-line treatment; for patients who achieve a satisfactory response, a consolidation by means of autologous stem cell transplantation may offer a greater chance of long-term survival...
March 2, 2017: Blood
https://www.readbyqxmd.com/read/28110187/insecticidal-activities-of-histone-deacetylase-inhibitors-against-a-dipteran-parasite-of-sheep-lucilia-cuprina
#18
Neil H Bagnall, Barney M Hines, Andrew J Lucke, Praveer K Gupta, Robert C Reid, David P Fairlie, Andrew C Kotze
Histone deacetylase inhibitors (HDACi) are being investigated for the control of various human parasites. Here we investigate their potential as insecticides for the control of a major ecto-parasite of sheep, the Australian sheep blowfly, Lucilia cuprina. We assessed the ability of HDACi from various chemical classes to inhibit the development of blowfly larvae in vitro, and to inhibit HDAC activity in nuclear protein extracts prepared from blowfly eggs. The HDACi prodrug romidepsin, a cyclic depsipeptide that forms a thiolate, was the most potent inhibitor of larval growth, with equivalent or greater potency than three commercial blowfly insecticides...
April 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28107750/effect-of-clinically-approved-hdac-inhibitors-on-plasmodium-leishmania-and-schistosoma-parasite-growth
#19
Ming Jang Chua, Megan S J Arnold, Weijun Xu, Julien Lancelot, Suzanne Lamotte, Gerald F Späth, Eric Prina, Raymond J Pierce, David P Fairlie, Tina S Skinner-Adams, Katherine T Andrews
Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L...
April 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28107222/romidepsin-induced-hiv-1-viremia-during-effective-art-contains-identical-viral-sequences-with-few-deleterious-mutations
#20
Anni Winckelmann, Kirston Barton, Bonnie Hiener, Timothy E Schlub, Wei Shao, Thomas A Rasmussen, Lars Østergaard, Ole S Søgaard, Martin Tolstrup, Sarah Palmer
OBJECTIVE: To investigate the origin of the HIV-1 viremia induced by the latency-reversing agent romidepsin. DESIGN: Six individuals on suppressive antiretroviral therapy received romidepsin administered intravenously once weekly for three consecutive weeks. CD4+ T-cells were obtained at baseline, following the second and third romidepsin infusion, and 10 weeks after the final romidepsin treatment. METHODS: Single-genome sequencing of the env region was used to genetically characterize the virus from proviral DNA, the transcribed cell-associated RNA and the plasma RNA pool...
January 19, 2017: AIDS
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