Romidepsin
Encyclopedia
Romidepsin codenamed FK228 and FR901228, is an anticancer agent undergoing clinical trial
s 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 deacetylase
s and inducing apoptosis
in tumor cells. 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
. 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
.
) 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
.
.
Phase II trials were conducted for a variety of indications, including prostate cancer
, multiple myeloma
, pancreatic cancer
, breast cancer
, ovarian cancer
, melanoma
, neuroendocrine tumors, and leukemia
s.
The most dramatic results were found in the treatment of cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphoma
s (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;
2009: FDA approval for CTCL was obtained on November 5, 2009.
, 3 phase II trials for multiple myeloma and peripheral T-cell lymphoma are still recruiting.
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
.
. 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.
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s as a treatment for cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma
Peripheral T-cell lymphoma
Peripheral T-cell lymphoma refers to a group of T-cell lymphomas that develop away from the thymus.Examples include:* Cutaneous T-cell lymphomas* Angioimmunoblastic T-cell lymphoma* Extranodal natural killer/T-cell lymphoma, nasal type...
, and a variety of other cancers. Romidepsin is a natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
obtained from the bacteria Chromobacterium violaceum
Chromobacterium violaceum
Chromobacterium violaceum is a Gram-negative, facultative anaerobic, non-sporing coccobacillus. It is part of the normal flora of water and soil of tropical and sub-tropical regions of the world. It produces a natural antibiotic called violacein, which may be useful for the treatment of colon and...
, and works by blocking enzymes known as histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
s and inducing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in tumor cells. It is sometimes referred to as depsipeptide
Depsipeptide
A depsipeptide is a peptide in which one or more of the amide bonds are replaced by ester bonds.Depsipeptides have often been used in research to probe the importance of hydrogen bond networks in protein folding kinetics and thermodynamics. They are also found in nature as natural products...
, after the class of molecules to which it belongs.
Romidepsin is branded and owned by Gloucester Pharmaceuticals, now a part of Celgene
Celgene
Celgene Corporation is a manufacturer of drug therapies for cancer and inflammatory disorders. It is incorporated in Delaware and headquartered in Summit, New Jersey...
. 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
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
.
History
Romidepsin was first reported in the scientific literature in 1994, by a team of researchers from Fujisawa Pharmaceutical Company (now Astellas PharmaAstellas Pharma
is a Japanese pharmaceutical company, formed on 1 April 2005 from the merger of and .Astellas' franchise areas are urology, immunology , dermatology, cardiology, and infectious disease...
) in Tsukuba
Tsukuba, Ibaraki
is a city located in Ibaraki Prefecture, Japan. It is known as the location of the , a planned city developed in the 1960s.As of 2008, the city has an estimated population of 207,394 and a population density of 730 persons per km². Its total area is 284.07 km².Mount Tsukuba, particularly well-known...
, Japan, who isolated it in a culture of Chromobacterium violaceum
Chromobacterium violaceum
Chromobacterium violaceum is a Gram-negative, facultative anaerobic, non-sporing coccobacillus. It is part of the normal flora of water and soil of tropical and sub-tropical regions of the world. It produces a natural antibiotic called violacein, which may be useful for the treatment of colon and...
from a soil sample obtained in Yamagata Prefecture
Yamagata Prefecture
-Fruit:Yamagata Prefecture is the largest producer of cherries and pears in Japan. A large quantity of other kinds of fruits such as grapes, apples, peaches, melons, persimmons and watermelons are also produced.- Demographics :...
. It was found to have little to no antibacterial activity, but was potently cytotoxic against several human cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cell lines
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
, with no effect on normal cells; studies on mice later found it to have antitumor activity in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
as well.
The first total synthesis
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
of romidepsin was accomplished by Harvard
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
researchers and published in 1996. Its mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
was elucidated in 1998, when researchers from Fujisawa and the University of Tokyo
University of Tokyo
, abbreviated as , is a major research university located in Tokyo, Japan. The University has 10 faculties with a total of around 30,000 students, 2,100 of whom are foreign. Its five campuses are in Hongō, Komaba, Kashiwa, Shirokane and Nakano. It is considered to be the most prestigious university...
found it to be a histone deacetylase inhibitor
Histone deacetylase inhibitor
Histone deacetylase inhibitors are a class of compounds that interfere with the function of histone deacetylase.HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics...
with effects similar to those of trichostatin A
Trichostatin A
Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase families of enzymes, but not class III HDACs . TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage...
.
Clinical trials
Phase I studies of romidepsin began in 1997, sponsored by the National Cancer InstituteNational Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
.
Phase II trials were conducted for a variety of indications, including prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
, pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
, melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, neuroendocrine tumors, and leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s.
The most dramatic results were found in the treatment of cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphoma
Peripheral T-cell lymphoma
Peripheral T-cell lymphoma refers to a group of T-cell lymphomas that develop away from the thymus.Examples include:* Cutaneous T-cell lymphomas* Angioimmunoblastic T-cell lymphoma* Extranodal natural killer/T-cell lymphoma, nasal type...
s (PTCLs).
In 2004, romidepsin received Fast Track
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
designation from the FDA for the treatment of cutaneous T-cell lymphoma, and orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
status from the FDA and the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
for the same indication;
2009: FDA approval for CTCL was obtained on November 5, 2009.
, 3 phase II trials for multiple myeloma and peripheral T-cell lymphoma are still recruiting.
Mechanism of action
Romidepsin acts as a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
with the disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
undergoing reduction
Reduction
Reduction, reduced, or reduce may refer to:- Chemistry :* Reduction, part of a reduction-oxidation reaction where oxygen is being removed from a compound.** Reduced gas, a gas with a low oxidation number...
within the cell to release a zinc-binding thiol
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
. The thiol reversibly interacts with a zinc atom in the binding pocket of Zn-dependent histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Adverse effects
The use of romidepsin is uniformly associated with adverse effectsAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
. In clinical trials, the most common were nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, fatigue, infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, loss of appetite
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, and blood disorders (including anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
, and leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
). It has also been associated with metabolic disturbances (such as abnormal electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
levels), skin reactions, altered taste perception
Dysgeusia
Dysgeusia is the distortion of the sense of taste. Dysgeusia is also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is the decrease in taste sensitivity. An alteration in taste or smell may be a secondary process in various disease states, or it may be...
, and changes in cardiac electrical conduction.
External links
- Clinical trials of romidepsin at ClinicalTrials.govClinicalTrials.govClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine at the National Institutes of Health, and is the largest clinical trials database, currently holding registrations from over 93,000 trials from more than 170 countries in the...