5-Azacytidine
Encyclopedia
Azacitidine or 5-azacytidine, sold under the trade name Vidaza, is a chemical analogue
of cytidine
, a nucleoside
present in DNA
and RNA
. Azacitidine and its deoxy derivative, decitabine (also known as 5-aza-2′deoxycytidine), are used in the treatment of myelodysplastic syndrome
. Both drugs were first synthesized in Czechoslovakia
as potential chemotherapeutic agent
s for cancer.
Azacitidine has also been used as an experimental treatment in clinical trials involving cases of acute myeloid leukemia
, where the patient has suffered more than one relapse- in these cases, standard chemotherapy, hematopoietic stem cell transplantation, and other mainline treatments have failed.
(MDS), for which it received approval by the U.S. Food and Drug Administration
on May 19, 2004; it is marketed as Vidaza. In a randomized controlled trial
comparing azacitidine to supportive treatment of MDS, around 16% of people receiving the drug had a complete or partial response—blood cell count
s and bone marrow
morphology returning to normal—and 2/3 patients who required blood transfusion
s before the study no longer needed them after receiving azacitidine.
It can also be used in vitro
to remove methyl groups from DNA
. This may weaken the effects of gene silencing mechanisms that occurred prior to the methylation. Methylation events are therefore believed to secure the DNA in a silenced state. Demethylation may reduce the stability of silencing signals and thus confer relative gene activation.
and into RNA
during transcription
in the cell. Azacitidine acts as a false substrate and potent inhibitor of methyltransferases leading to reduction of DNA methylation — affecting the way cell regulation proteins are able to bind to the DNA/RNA substrate. Inhibition of DNA methylation occurs through the formation of stable complexes between the molecule and with DNA methyltransferases, thereby saturating cell methylation machinery.
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of cytidine
Cytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
, a nucleoside
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
present in DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. Azacitidine and its deoxy derivative, decitabine (also known as 5-aza-2′deoxycytidine), are used in the treatment of myelodysplastic syndrome
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
. Both drugs were first synthesized in Czechoslovakia
Czechoslovakia
Czechoslovakia or Czecho-Slovakia was a sovereign state in Central Europe which existed from October 1918, when it declared its independence from the Austro-Hungarian Empire, until 1992...
as potential chemotherapeutic agent
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
s for cancer.
Azacitidine has also been used as an experimental treatment in clinical trials involving cases of acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
, where the patient has suffered more than one relapse- in these cases, standard chemotherapy, hematopoietic stem cell transplantation, and other mainline treatments have failed.
Uses
Azacitidine is mainly used in the treatment of myelodysplastic syndromeMyelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
(MDS), for which it received approval by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
on May 19, 2004; it is marketed as Vidaza. In a randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
comparing azacitidine to supportive treatment of MDS, around 16% of people receiving the drug had a complete or partial response—blood cell count
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
s and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
morphology returning to normal—and 2/3 patients who required blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s before the study no longer needed them after receiving azacitidine.
It can also be used in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
to remove methyl groups from DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. This may weaken the effects of gene silencing mechanisms that occurred prior to the methylation. Methylation events are therefore believed to secure the DNA in a silenced state. Demethylation may reduce the stability of silencing signals and thus confer relative gene activation.
Mechanism of action
Methyltransferases in the presence of azacitidine incorporate it into DNA during replicationDNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and into RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
during transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
in the cell. Azacitidine acts as a false substrate and potent inhibitor of methyltransferases leading to reduction of DNA methylation — affecting the way cell regulation proteins are able to bind to the DNA/RNA substrate. Inhibition of DNA methylation occurs through the formation of stable complexes between the molecule and with DNA methyltransferases, thereby saturating cell methylation machinery.