Romidepsin

Romidepsin

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
Licence data	US FDA:link
Pregnancy category	US: D (Evidence of risk)
Legal status	US: ℞-only
Routes of administration	Intravenous infusion
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
Molecular mass	540.695 g/mol
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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. 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.

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. 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.

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

Clinical trials

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

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

Mechanism of action

Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol. 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 restore normal expression of genes, which may result in cell cycle arrest, differentiation, and apoptosis.

Adverse effects

The use of romidepsin is uniformly associated with adverse effects. 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.

External links

• Clinical trials of romidepsin at ClinicalTrials.gov