On
page 175 Dr. Moalem discussed drugs that were designed to affect methylation patterns,
in addition to drugs that cause methylation. To give an example of one such
drug, he described azacitidine. This drug is used for the treatment of
myelodysplastic syndrome, or MDS.
Explain how azacitidine relates to methylation. Also, MDS is described
as a collection of blood disorders, therefore describe the major blood
disorders that comprise MDS and explain the symptoms. The relationship between
azacitidine and MDS relates to Big Idea 4 (Biological systems interact, and
these systems and their interactions possess complex properties) because
azacitidine and MDS interact to treat a patient.
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ReplyDeleteAccording to the Cancer Alliance for Research, Education, and Survivorship Institute (chemocare.com), Azacitidine is a cytotoxic anti-cancer chemotherapy drug. Azacitidine is used to treat myelodysplastic syndrome (MDS), which is a group of disorders "in which the bone marrow produces" (National Institutes of Health ) abnormal and low-count blood cells due to malfunction in bone marrow.
ReplyDeleteMethylation is a process where methyl groups attach to DNA and RNA, causing the chromatin to condense and causing DNA and RNA to be inhibited in transcription and translation, thus inhibiting gene expression to produce specific proteins necessary for cellular function. Chromatin condensation also inhibits transcription because transcription proteins cannot easily access the specific locations of the DNA to initiate transcription and gene expression (Campbell 358). Azacitidine is used to demethylate DNA and RNA, resulting in a less denser chromatin, allowing transcription proteins, including RNA polymerase, to more easily reach the DNA or to allow tRNA to more easily access mRNA (US National Library of Medicine ). Azacitidine also demethylates by removing methyl groups attached to the nucleic acids which results in chromatin decondensation. This relates to Big Idea 4 (Biological systems interact, and these systems and their interactions possess complex properties) in that methyl group molecules and Azacitidine interact with the nucleic acid systems (DNA, RNA, gene expression, and gene regulation) to control the level of gene expression to produce necessary proteins.
Myelodysplastic syndromes (MDS) can be mild or life-threatening, and it can also lead to severe leukemia. The major blod disorders that comprise MDS are refractory cytopenia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts 1 and 2, and 5q- syndrome (National Marrow Donor Program ). "Anemia is the most common symptom of MDS: feeling fatigue, shortness of breath, paleness, which is caused by low hemoglobin count. Other symptoms of MDS are fever and infrequent infections caused by low leukocyte (white blood cells) count, and easy bleeding and bruising caused by low platelet count. This also relates to Big Idea 4 (Biological systems interact, and these systems and their interactions possess complex properties) in that hemoglobin, leukocytes, and platelets are all components of the blood, respectively responsible for oxygen transport, part of immune response and phagocytosis of pathogens, and skin and blood vessel damage repair, malfunctioning of the bone marrow leads to abnormality in these blood components.
Paul Sone, jsone4@students.d125.org
Azacitidine helps to "inhibit the methylation of certain genes in the blood cells, helping to restore proper DNA function and reducing the risk that MDS will develop into leukemia" (126). Methylation is the process of adding a methyl group to a part of DNA or RNA, which causes chromatin in the nucleus to condense. This will affect gene expression because transcription or translation proteins will not be able to access parts of DNA or RNA that are methylated and tightly wound, and certain proteins will not be produced.
ReplyDeleteRather than methylating DNA, the drug actually prevents other factors from doing so in order to make sure that genes encoding for proteins that regulate blood are expressed to prevent blood disorders. Azacitidine is used to remove methyl groups from and loosen parts of DNA or RNA, and allow RNA polymerase or tRNA to more easily access parts of DNA or RNA, respectively, that were once tightly wound (Campbell 358). Azacitidine works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow (Medline Plus). Also, azacytidine is a ribonucleoside, so the primary target of this drug may be cellular RNA rather than DNA (PubMed). Studies with cancer patients have shown that azacytidine inhibits the RNA methyltransferase DNMT2, a family of enzymes that catalyze the transfer of a methyl group to DNA (US National Library of Medicine). The enzymes incorporate a methyl group into position 5 of a cytosine ring resulting in 5-methyl cytosine, and too much of this, especially at promoter regions, can causes diseases from excess gene silencing. Because of its interactions, azacitidine can be used as a cancer treatment drug in addition to MDS treatment (PubMed).
One blood disorder that can be brought on by MDS is anemia, which results in a lower red blood cell count or hemoglobin levels, and not enough oxygen will be delivered to the cells. Loss of blood is the most common cause of anemia, and the disorder can be temporary or long term ranging from mild to severe (Mayo Clinc: Anemia). Fatigue and shortness of breath can occur frequently because organs aren't getting enough oxygen to function properly. Pale skin may result due to fewer red blood cells. Dizziness can occur from reduced oxygen levels to the brain. And the heart my beat quickly or irregularly to circulate more blood though the body to maintain sufficient oxygen levels to all organs. These complications could lead to leukemia if severe. (Mayo Clinc: Anemia)
The use of azacitidine to demethylate DNA/RNA and treat MDS relates to Big Idea 4 (Biological systems interact, and these systems and their interactions possess complex properties) in that methyl groups on DNA/RNA interact with Azacitidine and systems of gene expression and regulation to control the phenotype of an organism and produce necessary proteins. Azacitidine can also interact with organ systems such as bone marrow from the skeletal system.
Sources:
“PubMed: Azacytidine inhibits RNA methylation” (http://www.ncbi.nlm.nih.gov/pubmed/19808971)
“Medline Plus: Azacitidine Injection” (http://www.nlm.nih.gov/medlineplus/druginfo/meds/a607068.html)
“US National Library of Medicine: Azacytidine (Vidaza®) in the treatment of myelodysplastic syndromes” (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936359/ )
“Mayo Clinc: Anemia” (http://www.mayoclinic.com/health/anemia/DS00321/DSECTION=symptoms)
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