関: 5-azacytidine、azacitidine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/08 03:33:56」(JST)

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Azacitidine (INN) 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 agents for cancer.^[2]

Uses

Azacitidine is mainly used in the treatment of myelodysplastic syndrome (MDS), for which it received approval by the U.S. Food and Drug Administration on May 19, 2004; it is marketed as Vidaza.^[3] 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 counts and bone marrow morphology returning to normal—and 2/3 patients who required blood transfusions before the study no longer needed them after receiving azacitidine.^[4]

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.^[5]

Borodovsky, et al. describe the dramatic effect of 5-azacytidine on IDH1 mutant glioma xenografts in mice.^[6]

Mechanism of action

Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside used in DNA and RNA. Azacitidine is thought to induce antineoplastic activity via two mechanisms; inhibition of DNA methyltransferase at low doses, causing hypomethylation of DNA, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA at high doses, resulting in cell death. As azacitidine is a ribonucleoside, it incorporates into RNA to a larger extent than into DNA. The incorporation into RNA leads to the dissembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of protein. Its incorporation into DNA leads to a covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequent cytotoxicity. Being a ribonucleoside, it has been shown effective against HIV ^[7] and HTLV.^[8]

Incorporation of azanucleosides (Azacitidine) into nucleic acids and DNA demethylation.

After azanucleosides (Azacitidine) have been metabolized to 5-aza-2′-deoxycytidine-triphosphate, they can become substrates for the DNA replication machinery and will be incorporated into DNA, where azacytosine can substitute for cytosine. Azacytosine-guanine dinucleotides are recognized by the DNA methyltransferases as natural substrate and the enzymes will initiate the methylation reaction by a nucleophilic attack. This results in the establishment of a covalent bond between the carbon-6 atom of the cytosine ring and the enzyme. The bond is normally resolved by beta-elimination through the carbon-5 atom, but the reaction is blocked with azacytosine, where carbon-5 is substituted by nitrogen. Thus, the enzyme remains covalently bound to DNA and its DNA methyltransferase function is blocked. In addition, the covalent protein adduction also compromises the functionality of DNA and triggers DNA damage signaling, resulting in the degradation of trapped DNA methyltransferases. As a consequence, methylation marks become lost during DNA replication.^[9]

References

^ Deglin, Judith, & Vallerand, April. (2009). Davis's drug guide for nurses. Philadelphia: F.A. Davis Company. pg. 204-206
^ Cihák A (1974). "Biological effects of 5-azacytidine in eukaryotes". Oncology 30 (5): 405–422. doi:10.1159/000224981. PMID 4142650.
^ Vidaza web site.
^ Kaminskas E, Farrell AT, Wang Y-C, Sridhara R, Pazdur R (2005). "FDA Drug Approval Summary: Azacitidine (5-azacytidine, Vidaza) for Injectable Suspension". The Oncologist 10 (3): 176–182. doi:10.1634/theoncologist.10-3-176. PMID 15793220.
^ Whitelaw E and Garrick D (2005), The Epigenome, Chapter 7, In: Mammalian Genomics, Ed: Ruvinsky A & Marshall Graves JA, CABI Publishing, Wallingford, UK, ISBN 0-85199-910-7.
^ Borodovsky, A, et al., "5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft", Oncotarget Advance Publications (2013)
^ 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1
^ Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations
^ Stresemann, C. and Lyko, F. (2008), Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer, 123: 8–13. doi:10.1002/ijc.23607.

External links

5-Aza-2'-Deoxycytidine information and protocols to study DNA methylation

UpToDate Contents

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1. 中等度～低リスクまたは極めて低リスクの骨髄異形成症候群の治療 treatment of intermediate low or very low risk myelodysplastic syndromes
2. 高齢者における急性骨髄性白血病の治療 treatment of acute myeloid leukemia in older adults
3. 高リスクまたは極めて高リスクの骨髄異形成症候群の治療 treatment of high or very high risk myelodysplastic syndromes
4. 骨髄異形成症候群の合併症のマネージメント management of the complications of the myelodysplastic syndromes
5. 治療関連骨髄腫瘍：急性骨髄性白血病および骨髄異形成症候群 therapy related myeloid neoplasms acute myeloid leukemia and myelodysplastic syndrome

English Journal

Azacitidine as the post-remission therapy for elderly patients with acute myeloid leukemia.

Yamamoto R1, Yokoyama A, Yoneda M, Ohashi K, Hosoda T, Kagoo T, Boku S, Ueno H, Yano T.
Annals of hematology.Ann Hematol.2014 Dec;93(12):2081-2. doi: 10.1007/s00277-014-2119-8. Epub 2014 May 27.
PMID 24863693

Hypomethylating agent 5-aza-2'-deoxycytidine (DAC) ameliorates multiple sclerosis in mouse models.

Mangano K1, Fagone P, Bendtzen K, Meroni PL, Quattrocchi C, Mammana S, Di Rosa M, Malaguarnera L, Coco M, Magro G, Di Marco R, Nicoletti F.
Journal of cellular physiology.J Cell Physiol.2014 Dec;229(12):1918-25. doi: 10.1002/jcp.24641.
Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5-aza-2'-deoxycytidine (DAC) in two mur
PMID 24700487

Toxic encephalopathy after exposure to azacitidine.

Watanabe K1, Doki N, Miura Y, Hagino T, Kurosawa S, Hino Y, Shingai N, Yoshioka K, Ishida S, Igarashi A, Najima Y, Kobayashi T, Kakihana K, Sakamaki H, Ohashi K.
Leukemia & lymphoma.Leuk Lymphoma.2014 Nov 5:1-2. [Epub ahead of print]
PMID 25224457

Japanese Journal

Different Effects of Epigenetic Modifiers on the Cytotoxicity Induced by 5-Fluorouracil, Irinotecan or Oxaliplatin in Colon Cancer Cells

Ikehata Mika,Ogawa Mao,Yamada Yasuki,Tanaka Shota,Ueda Kumiko,Iwakawa Seigo
Biological and Pharmaceutical Bulletin, 2014
… In SW480 cells, DNMT inhibitors, such as decitabine (DAC), azacytidine and zebularine (Zeb), showed synergic effects on the cytotoxicity induced by anticancer drugs except for SN-38 plus Zeb, while HDAC inhibitors, trichostatin A, suberoylanilide hydroxamic acid and valproic acid, showed antagonistic effects. …
NAID 130003382113

5-Azacytidine as a tool to induce somaclonal variants with useful traits in sugarcane (Saccharum spp.)

Munsamy Ashlin,Rutherford R. Stuart,Snyman Sandy J. [他]
Plant biotechnology reports 7(4), 489-502, 2013-10
NAID 40019926595

骨髄異形成症候群 : アザシチジンによる外来治療 (第5土曜特集抗がん剤外来治療コンセプトシート2013) -- (抗がん剤の外来治療と注意点 : 各論)

藤原慎一郎,永井正
医学のあゆみ 246(9), 678-682, 2013-08-31
NAID 40019759779

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★リンクテーブル★

リンク元	「アザシチジン」「azacitidine」

「アザシチジン」

Azacitidine
Systematic (IUPAC) name
	4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
Clinical data
Trade names	Vidaza
AHFS/Drugs.com	monograph
MedlinePlus	a607068
Pregnancy cat.	D (US), X (Aus)
Legal status	?
Routes	SubQ, IV
Pharmacokinetic data
Metabolism	possible hepatic metabolism, mostly urinary excretion
Half-life	4 hr.
Identifiers
CAS number	320-67-2
ATC code	L01BC07
PubChem	CID 9444
DrugBank	DB00928
ChemSpider	9072
UNII	M801H13NRU
KEGG	D03021
ChEBI	CHEBI:2038
ChEMBL	CHEMBL1489
Synonyms	5-azacytidine
Chemical data
Formula	C8H12N4O5
Mol. mass	244.205 g/mol
	SMILES O=C1/N=C(\N=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)CO)N;
	InChI InChI=1S/C8H12N4O5/c9-7-10-2-12(8(16)11-7)6-5(15)4(14)3(1-13)17-6/h2-6,13-15H,1H2,(H2,9,11,16)/t3-,4-,5-,6-/m1/s1 ; Key:NMUSYJAQQFHJEW-KVTDHHQDSA-N ;
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英: azacytidine、azacitidine
同: 5-アザシチジン
商: ビダーザ
関: その他の腫瘍用薬

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「azacitidine」

　　[★] アザシチジン

関: 5-azacytidine、azacytidine

[1] Deglin, Judith, & Vallerand, April. (2009). Davis's drug guide for nurses. Philadelphia: F.A. Davis Company. pg. 204-206

[2] Cihák A (1974). "Biological effects of 5-azacytidine in eukaryotes". Oncology 30 (5): 405–422. doi:10.1159/000224981. PMID 4142650.

[3] Vidaza web site.

[4] Kaminskas E, Farrell AT, Wang Y-C, Sridhara R, Pazdur R (2005). "FDA Drug Approval Summary: Azacitidine (5-azacytidine, Vidaza) for Injectable Suspension". The Oncologist 10 (3): 176–182. doi:10.1634/theoncologist.10-3-176. PMID 15793220.

[5] Whitelaw E and Garrick D (2005), The Epigenome, Chapter 7, In: Mammalian Genomics, Ed: Ruvinsky A & Marshall Graves JA, CABI Publishing, Wallingford, UK, ISBN 0-85199-910-7.

[6] Borodovsky, A, et al., "5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft", Oncotarget Advance Publications (2013)

[7] 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1

[8] Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations

[9] Stresemann, C. and Lyko, F. (2008), Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer, 123: 8–13. doi:10.1002/ijc.23607.

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azacytidine