Romidepsin

Last updated
Romidepsin
Romidepsin.svg
Romidepsin ball and spoke.png
Clinical data
Trade names Istodax
Other namesFK228; FR901228; Istodax
MedlinePlus a610005
License data
Routes of
administration 		Intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Not applicable (IV only)
Protein binding 92–94%
Metabolism Liver (mostly CYP3A4-mediated)
Elimination half-life 3 hours
Identifiers
  • (1S,4S,7Z,10S,16E,21R)-7-Ethylidene-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.211.884 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H36N4O6S2
Molar mass 540.69 g·mol−1
3D model (JSmol)
  • C/C=C\1/C(=O)N[C@H](C(=O)O[C@H]\2CC(=O)N[C@@H](C(=O)N[C@H](CSSCC/C=C2)C(=O)N1)C(C)C)C(C)C
  • InChI=1S/C24H36N4O6S2/c1-6-16-21(30)28-20(14(4)5)24(33)34-15-9-7-8-10-35-36-12-17(22(31)25-16)26-23(32)19(13(2)3)27-18(29)11-15/h6-7,9,13-15,17,19-20H,8,10-12H2,1-5H3,(H,25,31)(H,26,32)(H,27,29)(H,28,30)/b9-7+,16-6-/t15-,17-,19-,20+/m1/s1
  • Key:OHRURASPPZQGQM-GCCNXGTGSA-N
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Romidepsin, sold under the brand name Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum , and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. [2] It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, a part of Celgene. [3]

Contents

History

Romidepsin was first reported in the scientific literature in 1994, by a team of researchers from Fujisawa Pharmaceutical Company (now Astellas Pharma) in Tsukuba, Japan, who isolated it in a culture of Chromobacterium violaceum from a soil sample obtained in Yamagata Prefecture. [4] It was found to have little to no antibacterial activity, but was potently cytotoxic against several human cancer cell lines, with no effect on normal cells; studies on mice later found it to have antitumor activity in vivo as well. [4]

The first total synthesis of romidepsin was accomplished by Harvard researchers and published in 1996. [5] Its mechanism of action was elucidated in 1998, when researchers from Fujisawa and the University of Tokyo found it to be a histone deacetylase inhibitor with effects similar to those of trichostatin A. [6]

Clinical trials

Phase I studies of romidepsin, initially codenamed FK228 and FR901228, began in 1997. [7] Phase II and phase III trials were conducted for a variety of indications. The most significant results were found in the treatment of cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). [7]

In 2004, romidepsin received Fast Track designation from the FDA for the treatment of cutaneous T-cell lymphoma, and orphan drug status from the FDA and the European Medicines Agency for the same indication. [7]

The FDA approved romidepsin for CTCL in November 2009 [8] and approved romidepsin for other peripheral T-cell lymphomas (PTCLs) in June 2011. [9]

A randomised, phase III trial of romidepsin + CHOP chemotherapy vs CHOP chemotherapy for patients with peripheral T cell lymphoma returned negative results, having no significant impact on progression free survival or overall survival. [10]

Pre-clinical HIV study

In 2014, PLOS Pathogens published a study involving romidepsin in a trial designed to reactivate latent HIV virus in order to deplete the HIV reservoir. Latently infected T-cells were exposed in vitro and ex vivo to romidepsin, leading to an increase in detectable levels of cell-associated HIV RNA. The trial also compared the effect of romidepsin to another histone deacetylase inhibitor, Vorinostat [11]

Autism study in animal model

A study involving romidepsin in an animal study that showed that a brief treatment with low amounts of romidepsin could reverse social deficits in a mouse model of autism. [12]

Pharmacodynamics

In a Phase II trial of romidepsin involving patients with CTCL or PTCL, there was evidence of increased histone acetylation in peripheral blood mononuclear cells (PBMCs) extending 4–48 hours. Expression of the ABCB1 gene, a marker of romidepsin-induced gene expression, was also increased in both PBMCs and tumor biopsy samples. Increased gene expression following increased histone acetylation is an expected effect of an HDAC inhibitor. Increased hemoglobin F (another surrogate marker for gene-expression changes resulting from HDAC inhibition) was also detected in blood after romidepsin administration, and persistent histone acetylation was inversely associated with drug clearance and directly associated with patient response to therapy. [13]

Dosage and administration

The approved dosage of romidepsin in both CTCL and PTCL is a four-hour i.v. administration of 14 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle. [14] This cycle should be repeated as long as the patient continues to benefit and tolerate the therapy. A dose reduction to 10 mg/m2 is possible in some patients who experience high-grade toxicities.

Pharmacokinetics

In trials involving patients with advanced cancers, romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m2 when administered intravenously over four hours. [15] Age, race, sex, mild-to-severe renal impairment, and mild-to-moderate hepatic impairment had no effect on romidepsin pharmacokinetics. No accumulation of plasma concentration was observed after repeated dosing. [16]

Mechanism of action

Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol. [4] [17] [18] The thiol binds to a zinc atom in the binding pocket of Zn-dependent histone deacetylase to block its activity. Thus it is an HDAC inhibitor. Many HDAC inhibitors are potential treatments for cancer through the ability to epigenetically restore normal expression of tumor suppressor genes, which may result in cell cycle arrest, differentiation, and apoptosis. [19]

Adverse effects

The use of romidepsin is uniformly associated with adverse effects. [20] In clinical trials, the most common were nausea and vomiting, fatigue, infection, loss of appetite, and blood disorders (including anemia, thrombocytopenia, and leukopenia). It has also been associated with infections, and with metabolic disturbances (such as abnormal electrolyte levels), skin reactions, altered taste perception, and changes in cardiac electrical conduction. [20]

Related Research Articles

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.

<span class="mw-page-title-main">Cutaneous T-cell lymphoma</span> Medical condition

Cutaneous T-cell lymphoma (CTCL) is a class of non-Hodgkin lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin lymphomas, CTCL is caused by a mutation of T cells. The cancerous T cells in the body initially migrate to the skin, causing various lesions to appear. These lesions change shape as the disease progresses, typically beginning as what appears to be a rash which can be very itchy and eventually forming plaques and tumors before spreading to other parts of the body.

<span class="mw-page-title-main">Trichostatin A</span> Chemical compound

Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs. However, there are recent reports of the interactions of this molecule with Sirt 6 protein. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors that have a broad spectrum of epigenetic activities. Thus, TSA has some potential as an anti-cancer drug. One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer. Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.

<span class="mw-page-title-main">Tipifarnib</span> Chemical compound

Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.

Vorinostat (rINN) also known as Suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.

A depsipeptide is a peptide in which one or more of its amide, -C(O)NHR-, groups are replaced by the corresponding ester, -C(O)OR-. Many depsipeptides have both peptide and ester linkages. Elimination of the N–H group in a peptide structure results in a decrease of H-bonding capability, which is responsible for secondary structure and folding patterns of peptides, thus inducing structural deformation of the helix and b-sheet structures. Because of decreased resonance delocalization in esters relative to amides, depsipeptides have lower rotational barriers for cis-trans isomerization and therefore they have more flexible structures than their native analogs. They are mainly found in marine and microbial natural products.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">TopoTarget</span>

TopoTarget was a Copenhagen-based biotechnology company focused on the discovery and development of drugs and therapies to treat cancer. In 2014, it merged with BioAlliance Pharma and is now part of Onxeo.

<span class="mw-page-title-main">Panobinostat</span> Chemical compound

Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor.

<span class="mw-page-title-main">Belinostat</span> Pharmaceutical drug

Belinostat is a histone deacetylase inhibitor drug developed by TopoTarget for the treatment of hematological malignancies and solid tumors.

Subcutaneous T-cell lymphoma is a cutaneous condition that most commonly presents in young adults, and is characterized by subcutaneous nodules. Common symptoms include fever, fatigue, and pancytopenia.

<span class="mw-page-title-main">Mocetinostat</span> Chemical compound

Mocetinostat (MGCD0103) is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers including follicular lymphoma, Hodgkin's lymphoma and acute myelogenous leukemia.

Brentuximab vedotin, sold under the brand name Adcetris, is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL. The drug is being jointly marketed by Millennium Pharmaceuticals outside the US and by Seattle Genetics in the US.

<span class="mw-page-title-main">Abexinostat</span> Chemical compound

Abexinostat is an experimental drug candidate for cancer treatment. It was developed by Pharmacyclics and licensed to Xynomic. and is in Phase II clinical trials for B-cell lymphoma. Pre-clinical study suggests the potential for treatment of different types of cancer as well.

<span class="mw-page-title-main">Quisinostat</span> Chemical compound

Quisinostat is an experimental drug candidate for the treatment of cancer. It is a "second generation" histone deacetylase inhibitor with antineoplastic activity. It is highly potent against class I and II HDACs.

Resminostat is an orally bioavailable inhibitor of histone deacetylases (HDACs), of which inhibitors are antineoplastic agents.

<span class="mw-page-title-main">Tucidinostat</span> Chemical compound

Tucidinostat is a histone deacetylase inhibitor (HDI) developed in China. It was also known as HBI-8000. It is a benzamide HDI and inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10.

<span class="mw-page-title-main">Epigenetic priming</span> Type of modification to a cells epigenome

Epigenetic priming is the modification to a cell's epigenome whereby specific chromatin domains within a cell are converted from a closed state to an open state, usually as the result of an external biological trigger or pathway, allowing for DNA access by transcription factors or other modification mechanisms. The action of epigenetic priming for a certain region of DNA dictates how other gene regulation mechanisms will be able to act on the DNA later in the cell’s life. Epigenetic priming has been chiefly investigated in neuroscience and cancer research, as it has been found to play a key role in memory formation within neurons and tumor-suppressor gene activation in cancer treatment respectively.

Mature T-cell lymphoma, also called peripheral T-cell lymphoma, is a group of rare, aggressive lymphomas that develop from mature white blood cells and originate from lymphoid tissues outside of the bone marrow. Mature T-cell lymphoma is under the category of non-Hodgkin lymphoma. Mature T-cell lymphomas account for 10% to 15% of all lymphomas and is more common in Asia than in Europe and America. Its common subtypes include angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma and peripheral T-cell lymphoma not otherwise specified. While different subtypes have variable symptoms, common symptoms include enlarged painless lymph nodes, fever, weight loss, rash and night sweats.

References

  1. ↑ "Romidepsin-MSN, Romidepsin-Reach (Reach Pharmaceuticals Pty Ltd)". Therapeutic Goods Administration (TGA). 13 January 2023. Archived from the original on 18 March 2023. Retrieved 29 April 2023.
  2. ↑ "Romidepsin". National Cancer Institute. Archived from the original on 2009-05-09. Retrieved 2009-09-11.
  3. ↑ "Romidepsin". Gloucester Pharmaceuticals. Retrieved 2009-09-11.[ permanent dead link ]
  4. 1 2 3 Ueda H, Nakajima H, Hori Y, et al. (March 1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity". Journal of Antibiotics. 47 (3): 301–10. doi: 10.7164/antibiotics.47.301 . PMID   7513682.
  5. ↑ Li KW, Wu J, Xing W, Simon JA (July 1996). "Total synthesis of the antitumor depsipeptide FR-901,228". Journal of the American Chemical Society . 118 (30): 7237–8. doi:10.1021/ja9613724.
  6. ↑ Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S (May 1998). "FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor". Experimental Cell Research. 241 (1): 126–33. doi:10.1006/excr.1998.4027. PMID   9633520.
  7. 1 2 3 Masuoka Y, Shindoh N, Inamura N (2008). "Histone deacetylase inhibitors from microorganisms: the Astellas experience". In Petersen F, Amstutz R (eds.). Natural compounds as drugs. Vol. 2. Basel: Birkhäuser. pp. 335–59. ISBN   978-3-7643-8594-1. Retrieved on November 8, 2009 through Google Book Search.
  8. ↑ "New Drug Approvals - Pt. XXII - Romidepsin (Istodax)". Archived from the original on 2016-03-03. Retrieved 2009-12-03.
  9. ↑ "Drugs@FDA: FDA-Approved Drugs". Archived from the original on 2013-07-24. Retrieved 2015-08-31.
  10. ↑ "Final Analysis of the Ro-CHOP Phase III Study (Conducted by LYSA): Romidepsin Plus CHOP in Patients with Peripheral T-Cell Lymphoma". 5 December 2020. Archived from the original on 21 May 2021. Retrieved 21 May 2021.
  11. ↑ Wei, D; et al. (2014). "Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing". PLOS Pathog. 10 (4): e1004071. doi:10.1371/journal.ppat.1004071. PMC   3983056 . PMID   24722454.
  12. ↑ Qin, Luye; Ma, Kaijie; Wang, Zi-Jun; Hu, Zihua; Matas, Emmanuel; Wei, Jing; Yan, Zhen (2018). "Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition". Nature Neuroscience. 21 (4): 564–575. doi:10.1038/s41593-018-0110-8. PMC   5876144 . PMID   29531362.
  13. ↑ Bates, Susan E.; Zhan, Zhirong; Steadman, Kenneth; Obrzut, Tomasz; Luchenko, Victoria; Frye, Robin; Robey, Robert W.; Turner, Maria; Gardner, Erin R. (January 2010). "Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma". British Journal of Haematology. 148 (2): 256–267. doi:10.1111/j.1365-2141.2009.07954.x. ISSN   0007-1048. PMC   2838427 . PMID   19874311.
  14. ↑ Nakajima, Hidenori; Kim, Young Bae; Terano, Hiroshi; Yoshida, Minoru; Horinouchi, Sueharu (May 1998). "FR901228, a Potent Antitumor Antibiotic, Is a Novel Histone Deacetylase Inhibitor". Experimental Cell Research. 241 (1): 126–133. doi:10.1006/excr.1998.4027. ISSN   0014-4827. PMID   9633520.
  15. ↑ Bradner, James E; West, Nathan; Grachan, Melissa L; Greenberg, Edward F; Haggarty, Stephen J; Warnow, Tandy; Mazitschek, Ralph (2010-02-07). "Chemical phylogenetics of histone deacetylases". Nature Chemical Biology. 6 (3): 238–243. doi:10.1038/nchembio.313. ISSN   1552-4450. PMC   2822059 . PMID   20139990.
  16. ↑ Nakajima, Hidenori; Kim, Young Bae; Terano, Hiroshi; Yoshida, Minoru; Horinouchi, Sueharu (May 1998). "FR901228, a Potent Antitumor Antibiotic, Is a Novel Histone Deacetylase Inhibitor". Experimental Cell Research. 241 (1): 126–133. doi:10.1006/excr.1998.4027. ISSN   0014-4827. PMID   9633520.
  17. ↑ Shigematsu, N.; Ueda, H.; Takase, S.; Tanaka, H.; Yamamoto, K.; Tada, T. (1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. II. Structure determination". J. Antibiot. 47 (3): 311–314. doi: 10.7164/antibiotics.47.311 . PMID   8175483.
  18. ↑ Ueda, H.; Manda, T.; Matsumoto, S.; Mukumoto, S.; Nishigaki, F.; Kawamura, I.; Shimomura, K. (1994). "FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice". J. Antibiot. 47 (3): 315–323. doi: 10.7164/antibiotics.47.315 . PMID   8175484.
  19. ↑ Greshock, Thomas J.; Johns, Deidre M.; Noguchi, Yasuo; Williams, Robert M. (2008). "Improved Total Synthesis of the Potent HDAC Inhibitor FK228 (FR-901228)". Organic Letters. 10 (4): 613–616. doi:10.1021/ol702957z. PMC   3097137 . PMID   18205373.
  20. 1 2 "Istodax- romidepsin kit". DailyMed. 30 July 2021. Archived from the original on 26 November 2022. Retrieved 29 April 2023.
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