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Emerging Highlights on Natural Prodrug Molecules with Multifarious Therapeutic Perspectives
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Mojabir Hussen Ansari, Vaibhav Shende, Debarshi Kar Mahapatra
Romidepsin is a bicyclic depsipeptide that was first isolated from a Gram-negative rod-shaped single polar flagellum bacteria Chromobacterium violaceum.16 In early 1990s, romidepsin remained an important fermentation product for treating tumor (histone deacetylase class-I inhibitor; however, the mechanism is not fully known) forms such as glioblastoma, leukemia, lymphoma, myeloma, and breast, colorectal, gastrointestinal, lung, ovarian, pancreatic, and prostate cancer and also for treating the microbial infections.17 It is a prodrug that requires a reduction of its disulfide bonds to activate its less stable form. Histone acetyltransferases and histone deacetylases control histone acetylation by the way of direct addition of acetyl groups to the lysine residues within the amino-terminal histone tails, which neutralizes the part of the protein and relaxes the chromatin structure.18 Romidepsin is also classified as an epigenetic agent that introduces stable genetic changes by interfering with the gene expression and their function, without any corresponding changes in the DNA sequence.19 In recent years, small molecules of histone deacetylase (HDAC) inhibitors have owned the position of strong anticancer agents, many of which are now FDA approved anticancer agents, which have challenged the position of romidepsin.20
Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Approaches in relapsed/refractory disease are diverse and include (i) the histone deacetylase inhibitor romidepsin which has demonstrated clinical activity alone or in combinations,104 (ii) hypomethylating agents (e.g., azacytidine) given the observation of mutation in genes controlling epigenetic regulation, and (iii) the use of immunomodulatory therapies such as cyclosporin.105
The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Clearly, romidepsin has emerged as a promising HDAC inhibitor with significant activity in patients with both CTCL and PTCL. Continued studies in these diseases will better clarify the role of romidepsin in these difficult diseases. Other macrolide HDAC inhibitors include apicidin, an antiprotozoal fungal metabolite found to have HDAC inhibitory activity (73). Apicidin produced significant cell cycle arrest and induced apoptosis in a variety of cell lines, including drug-resistant leukemia cells. Similar results have been attained in experiments with cyclic hydroxamic acid–containing peptides (CHAPs) and chlamydocin.
Safety considerations with the current treatments for peripheral T-cell lymphoma
Published in Expert Opinion on Drug Safety, 2022
Tarsheen Sethi, Francesca Montanari, Francine Foss
Romidepsin is a potent class I HDAC inhibitor with a heterocyclic structure. A phase II trial of romidepsin was conducted in patients with R/R PTCL [22] with the drug given intravenously at a dose of 14 mg/m2 weekly for 3 weeks on a 28-day cycle. The ORR was 25% (33/130 patients), including 15% with CR. At a median follow-up of 22.3 months, the median DOR was 28 months. Most common toxicities included nausea, fatigue, infections, and thrombocytopenia. Grade 3/4 AEs were thrombocytopenia (grade 4 in 7%), neutropenia (grade 4 in 6%), and infection of any type. Infections of any grade occurred in 55% of patients and involved the upper respiratory tract infection (8%), urinary tract infection (7%) and sepsis (5%). An increased risk of grade 3/4 infections was seen with use of prior alemtuzumab or other monoclonal antibody therapy (30% v 14%) and in those with bone marrow involvement (30% v 12%). AEs leading to treatment discontinuation were seen in 25 (19%) of 131 patients (10% due to treatment-related AEs) and included thrombocytopenia and pneumonia (three patients each; 2%) and fatigue, dyspnea, and sepsis (two patients each; 2%).
New nonchemotherapy treatment options for cutaneous T-cell lymphomas
Published in Expert Review of Anticancer Therapy, 2021
Romidepsin is approved in the United States for the treatment of relapsed or refractory CTCL and peripheral T-cell lymphoma (PTCL)[78]. Two phase II trials enrolled patients with CTCL and administered 14 mg/m2 as an IV infusion on days 1, 8, and 15 of a 28 day cycle[79,80]. They reported similar ORR of 33% and 34% (28/84 and 33/96) and similar complete response rates of 5% and 6% (5/84 and 6/96), respectively[80,81]. The pivotal phase II trial noted that 43% (28/65) patients experienced clinically meaningful improvement in pruritus, including patients without an objective disease response[80]. Patients received cardiac monitoring due to reported cardiac toxicity in preclinical data and reversible ECG changes with ST/T wave flattening during phase I[82]. Both phase II trials reported small reversible QTc prolongation, but no evidence of drug-related cardiac damage[80,81]. However, both trials did adopt protocols to exclude patients at risk for sudden death and patients receiving QTc-prolonging or CYP3A4-inhibiting drugs.
Novel synthetic drugs for the treatment of non-Hodgkin lymphoma
Published in Expert Opinion on Pharmacotherapy, 2021
Farheen Manji, Robert Puckrin, Douglas A. Stewart
Histone deacetylase (HDAC) inhibitors exert their anti-neoplastic effect by modulating the acetylation of histone and transcription factor proteins, ultimately leading to cell cycle arrest and apoptosis [96]. The HDAC inhibitor romidepsin received accelerated U.S. FDA approval in 2011 for the treatment of relapsed/refractory PTCL after ≥1 line of therapy. Phase II studies in this poor-prognosis population demonstrated ORR 25–38%, CR rate 15–18%, and mDOR of 9–17mo [97,98]. Romidepsin is dosed at 14 mg/m2 weekly for 3 doses in 28-day treatment cycles which may be continued until disease progression or unacceptable toxicity. Drug interactions with warfarin and CYP3A inducers and inhibitors should be noted. Common adverse reactions include cytopenias, QT prolongation and other electrocardiogram changes, infection, gastrointestinal upset, and fatigue [99]. Romidepsin is currently under study as maintenance therapy following autotransplant for PTCL (NCT01908777), and in combination with lenalidomide (NCT01755975), the folate antagonist pralatrexate (NCT01947140), and the immune checkpoint inhibitor pembrolizumab (NCT03278782) for relapsed/refractory NHLs.