Romidepsin

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Romidepsin (INN, trade name Istodax), codenamed FK228 and FR901228, is an anticancer agent undergoing clinical trials as a treatment for cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, and a variety of other cancers. Romidepsin is a natural product obtained from the bacteria Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases and 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] On November 5, 2009, it was approved by the U.S. Food and Drug Administration for the treatment of CTCL, after five years in the agency's fast track development program.

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.[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

Phase I studies of romidepsin began in 1997, sponsored by the National Cancer Institute.[6]

Phase II trials were conducted for a variety of indications, including prostate cancer, multiple myeloma, pancreatic cancer,[6] breast cancer,[7] ovarian cancer,[8] melanoma,[9] neuroendocrine tumors,[10] and leukemias.[11] The most dramatic 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]

2009: FDA approval for CTCL was obtained on November 5, 2009.[12]

As of November 2009, 3 phase II trials for multiple myeloma and peripheral T-cell lymphoma are still recruiting.[13][14][15]

Mechanism of action

Romidepsin acts as a prodrug with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol.[3][16][17] 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.[18]

Adverse effects

The use of romidepsin is uniformly associated with adverse effects.[19] 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 metabolic disturbances (such as abnormal electrolyte levels), skin reactions, altered taste perception, and changes in cardiac electrical conduction.[19]

References

  1. 3.0 3.1 3.2
  2. 6.0 6.1 6.2 6.3 Retrieved on November 8, 2009 through Google Book Search.
  3. Clinical trial number NCT00098397 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  4. Clinical trial number NCT00085527 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  5. Clinical trial number NCT00104884 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  6. Clinical trial number NCT00084461 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  7. Clinical trial number NCT00062075 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  8. http://chembl.blogspot.com/2009/11/new-drug-approvals-pt-xxiii-romidepsin.html
  9. Clinical trial number NCT00765102 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  10. Clinical trial number NCT00426764 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  11. Clinical trial number NCT00924378 at ClinicalTrials.gov. Retrieved on November 8, 2009.
  12. 19.0 19.1

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See also

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