Romidepsin

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Romidepsin
Skeletal formula of (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
Romidepsin ball and spoke.png
Systematic (IUPAC) name
(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
Clinical data
Trade names Istodax
MedlinePlus a610005
License data
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
Intravenous infusion
Legal status
Legal status
Pharmacokinetic data
Bioavailability Not applicable (IV only)
Protein binding 92–94%
Metabolism Hepatic (mostly CYP3A4-mediated)
Biological half-life 3 hours
Identifiers
CAS Number 128517-07-7 N
ATC code none
PubChem CID 5352062
IUPHAR/BPS 7006
UNII CX3T89XQBK N
ChEBI CHEBI:61080 N
ChEMBL CHEMBL1213490 N
Synonyms FK228; FR901228; Istodax
Chemical data
Formula C24H36N4O6S2
Molar mass 540.695 g/mol
 NYesY (what is this?)  (verify)

Romidepsin, also known as 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 bacteria Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis.[1] It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, now a part of Celgene.[2]

History[edit]

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.[3] 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.[3]

The first total synthesis of romidepsin was accomplished by Harvard researchers and published in 1996.[4] 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.[5]

Clinical trials[edit]

Phase I studies of romidepsin, initially codenamed FK228 and FR901228, began in 1997.[6] 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).[6]

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.[6] The FDA approved romidepsin for CTCL in November 2009[7] and approved romidepsin for other peripheral T-cell lymphomas (PTCLs) in June 2011.[8]

Mechanism of action[edit]

Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol.[3][9][10] The thiol reversibly interacts with 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.[11]

Adverse effects[edit]

The use of romidepsin is uniformly associated with adverse effects.[12] 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.[12]

References[edit]

  1. ^ "Romidepsin". National Cancer Institute. Retrieved 2009-09-11. 
  2. ^ "Romidepsin". Gloucester Pharmaceuticals. Retrieved 2009-09-11. 
  3. ^ a b c 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ a b c Masuoka Y, Shindoh N, Inamura N (2008). "Histone deacetylase inhibitors from microorganisms: the Astellas experience". In Petersen F, Amstutz R. Natural compounds as drugs. 2. Basel: Birkhäuser. pp. 335–59. ISBN 978-3-7643-8594-1.  Retrieved on November 8, 2009 through Google Book Search.
  7. ^ http://chembl.blogspot.com/2009/11/new-drug-approvals-pt-xxiii-romidepsin.html
  8. ^ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.MonthlyApprovalsAll
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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 3097137free to read. PMID 18205373. 
  12. ^ a b [No authors listed] (October 2014). "ISTODEX Label Information (updated to October 2014)" (PDF). U.S. Food and Drug Administration. 

External links[edit]