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A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.
In biochemistry, the DNA methyltransferase family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.
Azacitidine, sold under the brand name Vidaza among others, is a medication used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.
Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.
Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.
Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog.
Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysine 4 (H3K4). Other reported methylated lysine substrates such as histone H3K9 and TP53 have not been biochemically validated. This enzyme plays a critical role in oocyte growth, embryogenesis, hematopoiesis and tissue-specific differentiation. LSD1 was the first histone demethylase to be discovered though more than 30 have since been described.
Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.
Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.
Demethylating agents are chemical substances that can inhibit methylation, resulting in the expression of the previously hypermethylated silenced genes. Cytidine analogs such as 5-azacytidine (azacitidine) and 5-azadeoxycytidine (decitabine) are the most commonly used demethylating agents. They work by inhibiting DNA methyltransferases. Both compounds have been approved in the treatment of myelodysplastic syndrome (MDS) by Food and Drug Administration (FDA) in United States. Azacitidine and decitabine are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given orphan drug status. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. There are many other demethylating agents that can be used to inhibit the growth of other diseases.
Sapacitabine is a chemotherapeutic drug developed by US biotechnology firm Cyclacel currently undergoing clinical trials against leukemia.
Omacetaxine mepesuccinate, formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML).
Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.
Vadastuximab talirine is an antibody-drug conjugate (ADC) directed to CD33 (siglec-3) which is a transmembrane receptor expressed on cells of myeloid lineage. The experimental drug, being developed by Seattle Genetics, was in clinical trials for the treatment of acute myeloid leukemia (AML).
Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.
Tazemetostat, sold under the brand name Tazverik, is a medication used for the treatment of adults and adolescents aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Epigenetic priming is the modification to a cell's epigenome whereby specific chromatin domains within a cell are converted from a closed state to an open state, usually as the result of an external biological trigger or pathway, allowing for DNA access by transcription factors or other modification mechanisms. The action of epigenetic priming for a certain region of DNA dictates how other gene regulation mechanisms will be able to act on the DNA later in the cell’s life. Epigenetic priming has been chiefly investigated in neuroscience and cancer research, as it has been found to play a key role in memory formation within neurons and tumor-suppressor gene activation in cancer treatment respectively.
References
- ↑ Garcia-Manero G (November 2008). "Demethylating agents in myeloid malignancies". Curr Opin Oncol. 20 (6): 705–10. doi:10.1097/CCO.0b013e328313699c. PMC 3873866 . PMID 18841054.
- ↑ Hambach L, Ling KW, Pool J, et al. (December 2008). "Hypomethylating drugs convert HA-1 negative solid tumors into targets for stem cell based immunotherapy". Blood. 113 (12): 2715–22. doi: 10.1182/blood-2008-05-158956 . PMID 19096014. Archived from the original on 2013-04-14.
- ↑ "Azacitadine - National Cancer Institute". NCI. September 17, 2014.
- ↑ "Decitabine - National Cancer Institute". NCI. May 19, 2011.
- ↑ Aribi A, Borthakur G, Ravandi F, et al. (February 2007). "Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia". Cancer. 109 (4): 713–7. doi: 10.1002/cncr.22457 . PMID 17219444.
- ↑ De Padua Silva L, de Lima M, Kantarjian H, et al. (January 2009). "Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome". Bone Marrow Transplant. 43 (11): 839–43. doi:10.1038/bmt.2008.400. PMID 19151791.
- ↑ "EC Approves Marketing Authorization Of DACOGEN For Acute Myeloid Leukemia". 2012-09-28. Retrieved 28 September 2012.
- ↑ Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S (September 2008). "A pilot pharmacokinetic study of oral azacitidine". Leukemia. 22 (9): 1680–4. doi:10.1038/leu.2008.145. PMID 18548103.
- ↑ Herman, J. G.; Baylin, S. B. (2003). "Gene silencing in cancer in association with promoter hypermethylation". New England Journal of Medicine. 349 (21): 2042–54. doi:10.1056/NEJMra023075. PMID 14627790.
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