Romidepsin
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Romidepsin, also known as Istodax, is an
anticancer agent Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
used in
cutaneous T-cell lymphoma 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 (which are generally B-cell-related), CTCL is caused by a mutation of T cells. The cancerous ...
(CTCL) and other
peripheral T-cell lymphoma Peripheral T-cell lymphoma refers to a group of T-cell lymphomas that develop away from the thymus or bone marrow. Examples include: * Cutaneous T-cell lymphomas * Angioimmunoblastic T-cell lymphoma * Extranodal natural killer/T-cell lymphoma, nas ...
s (PTCLs). Romidepsin is a
natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...
obtained from the bacterium ''
Chromobacterium violaceum ''Chromobacterium violaceum'' is a Gram-negative, facultative anaerobic, non-sporing coccobacillus. It is motile with the help of a single flagellum which is located at the pole of the coccobacillus. Usually, there are one or two more lateral f ...
'', and works by blocking enzymes known as
histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
s, thus inducing
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. It is sometimes referred to as
depsipeptide 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 ...
, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, now a part of
Celgene Celgene Corporation is a pharmaceutical company that makes cancer and immunology drugs. Its major product is Revlimid ( lenalidomide), which is used in the treatment of multiple myeloma, and also in certain anemias. The company is incorporated in ...
.


History

Romidepsin was first reported in the scientific literature in 1994, by a team of researchers from Fujisawa Pharmaceutical Company (now
Astellas Pharma is a Japanese multinational pharmaceutical company, formed on 1 April 2005 from the merger of and . On February 5, 2020, the company announced management changes effective from April 1, 2020. Astellas is a member of the Mitsubishi UFJ Finan ...
) in
Tsukuba is a city located in Ibaraki Prefecture, Japan. , the city had an estimated population of 244,528 in 108,669 households and a population density of 862 persons per km². The percentage of the population aged over 65 was 20.3%. The total ar ...
, Japan, who isolated it in a culture of ''
Chromobacterium violaceum ''Chromobacterium violaceum'' is a Gram-negative, facultative anaerobic, non-sporing coccobacillus. It is motile with the help of a single flagellum which is located at the pole of the coccobacillus. Usually, there are one or two more lateral f ...
'' from a soil sample obtained in
Yamagata Prefecture is a prefecture of Japan located in the Tōhoku region of Honshu. Yamagata Prefecture has a population of 1,079,950 (1 June 2019) and has a geographic area of 9,325 km² (3,600 sq mi). Yamagata Prefecture borders Akita Prefecture to the north, ...
. It was found to have little to no antibacterial activity, but was potently
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
against several human
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
cell lines An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cells ...
, with no effect on normal cells; studies on mice later found it to have antitumor activity ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' as well. The first
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
of romidepsin was accomplished by
Harvard Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher le ...
researchers and published in 1996. Its
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
was elucidated in 1998, when researchers from Fujisawa and the
University of Tokyo , abbreviated as or UTokyo, is a public research university located in Bunkyō, Tokyo, Japan. Established in 1877, the university was the first Imperial University and is currently a Top Type university of the Top Global University Project by ...
found it to be a
histone deacetylase inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...
with effects similar to those of
trichostatin A 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 (i.e., sirtuins). However, there are ...
.


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 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 (which are generally B-cell-related), CTCL is caused by a mutation of T cells. The cancerous ...
(CTCL) and other
peripheral T-cell lymphoma Peripheral T-cell lymphoma refers to a group of T-cell lymphomas that develop away from the thymus or bone marrow. Examples include: * Cutaneous T-cell lymphomas * Angioimmunoblastic T-cell lymphoma * Extranodal natural killer/T-cell lymphoma, nas ...
s (PTCLs). In 2004, romidepsin received
Fast Track The fast track is an informal English term meaning "the quickest and most direct route to achievement of a goal, as in competing for professional advancement". By definition, it implies that a less direct, slower route also exists. Fast track or F ...
designation from the FDA for the treatment of cutaneous T-cell lymphoma, and
orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...
status from the FDA and the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
for the same indication. The FDA approved romidepsin for CTCL in November 2009 and approved romidepsin for other
peripheral T-cell lymphoma Peripheral T-cell lymphoma refers to a group of T-cell lymphomas that develop away from the thymus or bone marrow. Examples include: * Cutaneous T-cell lymphomas * Angioimmunoblastic T-cell lymphoma * Extranodal natural killer/T-cell lymphoma, nas ...
s (PTCLs) in June 2011. A randomised, phase III trial of romidepsin + CHOP chemotherapy vs CHOP chemotherapy for patients with
peripheral T cell lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
returned negative results, having no significant impact on progression free survival or overall survival.


Pre-clinical HIV study

In 2014,
PLOS Pathogens ''PLOS Pathogens'' is a peer-reviewed open-access medical journal. All content in ''PLOS Pathogens'' is published under the Creative Commons "by-attribution" license. ''PLOS Pathogens'' began operation in September 2005. It was the fifth journal o ...
published a study involving romidepsin in a trial designed to reactivate latent HIV virus in order to deplete the HIV reservoir. Latently infected
T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
s were exposed
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
and
ex vivo ''Ex vivo'' (Latin: "out of the living") literally means that which takes place outside an organism. In science, ''ex vivo'' refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal ...
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 Vorinostat (rINN) also known as Suberoylanilide hydroxamic acid ( suberoyl+anilide+hydroxamic acid abbreviated as SAHA) is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) ha ...


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.


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.


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. 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. 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.


Mechanism of action

Romidepsin acts as a
prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
with the
disulfide bond In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
undergoing reduction within the cell to release a zinc-binding
thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
. The thiol binds to a zinc atom in the binding pocket of Zn-dependent
histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
to block its activity. Thus it is an
HDAC inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are be ...
. Many
HDAC inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are be ...
s 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.


Adverse effects

The use of romidepsin is uniformly associated with
adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...
. In clinical trials, the most common were
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
and
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...
,
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
,
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
,
loss of appetite Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...
, and blood disorders (including
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
,
thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
, and
leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...
). It has also been associated with infections, and with metabolic disturbances (such as abnormal
electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
levels), skin reactions, altered taste perception, and changes in cardiac electrical conduction.


References


External links


Clinical trials of romidepsin
at
ClinicalTrials.gov ClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine (NLM) at the National Institutes of Health, and is the largest clinical trials database, holding registrations from over 329,000 tri ...
{{HDAC inhibitors Antineoplastic drugs Bristol Myers Squibb Orphan drugs Prodrugs Histone deacetylase inhibitors Depsipeptides Astellas Pharma