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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/27 22:49:44」(JST)

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Vorinostat (rINN) or suberoylanilide hydroxamic acid (SAHA) is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.

Vorinostat is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after treatment with other medicines.^[1]

Approvals and indications

Vorinostat was the first histone deacetylase inhibitor^[2] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006. It is manufactured by Patheon, Inc., in Mississauga, Ontario, Canada, for Merck & Co., Inc., White House Station, New Jersey.^[3]

Mechanism of action

Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for Zinc ions also found in the active site of histone deacetylases ^[4] Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation. ^[4]

Clinical trials

Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.^[5]

A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4 - 4.4 months in earlier studies).^[6] Further brain tumor trials are planned in which vorinostat will be combined with other drugs.

Including vorinostat in treatment of advanced non-small-cell lung cancer (NSCLC) showed improved response rates and increased median progression free survival and overall survival (although the survival improvements were not significant at the P=0.05 level).^[7]

It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with Idarubicin and Cytarabine.^[8]

Preclinical investigations

Vorinostat is an interesting target for scientists interested in eradicating HIV from infected persons.^[9] Vorinostat was recently shown to have both in vitro and in vivo effects against latently HIV infected T-Cells.^[10]^[11]

References

^ "ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration" (Press release). Merck & Co.. June 7, 2006. http://www.merck.com/newsroom/press_releases/research_and_development/2006_0607.html. Retrieved 2006-10-06.
^ HDAC Inhibitors Base (vorinostat)
^ "FDA Approves New Drug for Skin Cancer, Zolinza" (Press release). Food and Drug Administration. October 6, 2006. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108758.htm. Retrieved 2006-10-06.
^ ^a ^b Richon, Victoria. "Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor". British Journal of Cancer. http://www.nature.com/bjc/journal/v95/n1s/full/6603463a.html. Retrieved 3 May 2012.
^ Cuneo A, Castoldi. "Mycosis fungoides/Sezary's syndrome". http://atlasgeneticsoncology.org/Anomalies/MycosFungID2039.html. Retrieved 2008-02-15.
^ "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. http://www.eurekalert.org/pub_releases/2007-06/mc-vsa053007.php. Retrieved 2007-06-03.
^ http://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html Dec 2009. URL dead Jan 2012
^ "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)". http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/.
^ "Study of the Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART". ClinicalTrials.gov. 2011-03-21. http://www.clinicaltrials.gov/ct2/show/NCT01319383.
^ Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM (2009). "Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid.". AIDS Res Hum Retroviruses 25 (2): 207–12. doi:10.1089/aid.2008.0191. PMC 2853863. PMID 19239360. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2853863/.
^ Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J et al. (2009). "Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells.". J Biol Chem 284 (11): 6782–9. doi:10.1074/jbc.M807898200. PMC 2652322. PMID 19136668. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2652322/.

External links

Vorinostat bound to proteins in the PDB

UpToDate Contents

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1. セザリー症候群の治療 treatment of sezary syndrome
2. 進行期（ステージIIB～IV）の菌状息肉症の治療 treatment of advanced stage iib to iv mycosis fungoides
3. 肝疾患を有する患者における化学療法による肝毒性および用量調整 chemotherapy hepatotoxicity and dose modification in patients with liver disease
4. 再発性または難治性の末梢性T細胞リンパ腫の治療 treatment of relapsed or refractory peripheral t cell lymphoma
5. 再発性または難治性の急性骨髄性白血病の治療 treatment of relapsed or refractory acute myeloid leukemia

English Journal

A cyclodextrin-capped histone deacetylase inhibitor.

Amin J, Puglisi A, Clarke J, Milton J, Wang M, Paranal RM, Bradner JE, Spencer J.SourceDept. of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, East Sussex, UK. Electronic address: j.amin@sussex.ac.uk.
Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2013 Jun 1;23(11):3346-8. doi: 10.1016/j.bmcl.2013.03.084. Epub 2013 Apr 2.
We have synthesized a β-cyclodextrin (βCD)-capped histone deacetylase (HDAC) inhibitor 3 containing an alkyl linker and a zinc-binding hydroxamic acid motif. Biological evaluation (HDAC inhibition studies) of 3 enabled us to establish the effect of replacing an aryl cap (in SAHA (vorinostat,)) 1 b
PMID 23591111

Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate.

Karube K, Tsuzuki S, Yoshida N, Arita K, Kato H, Katayama M, Ko YH, Ohshima K, Nakamura S, Kinoshita T, Seto M.SourceDivision of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
Cancer letters.Cancer Lett.2013 Jun 1;333(1):47-55. doi: 10.1016/j.canlet.2012.12.022. Epub 2013 Jan 21.
NK cell neoplasms are lymphoid malignancies with an aggressive clinical course. In the present study, we analyzed gene expression profiling of NK cell neoplasms and attempted to identify important molecular pathways and new effective drugs. Pathway analysis of gene expression profiles suggested the
PMID 23348693

Effects of combination therapy with dipeptidyl peptidase-IV and histone deacetylase inhibitors in the non-obese diabetic mouse model of type 1 diabetes.

Cabrera SM, Colvin SC, Tersey SA, Maier B, Nadler JL, Mirmira RG.SourceDepartment of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN.
Clinical and experimental immunology.Clin Exp Immunol.2013 Jun;172(3):375-82. doi: 10.1111/cei.12068.
Type 1 diabetes (T1D) results from T helper type 1 (Th1)-mediated autoimmune destruction of insulin-producing β cells. Novel experimental therapies for T1D target immunomodulation, β cell survival and inflammation. We examined combination therapy with the dipeptidyl peptidase-IV inhibitor MK-626 a
PMID 23600825

Japanese Journal

Vorinostatで加療したSézary症候群の1例

Skin Cancer 30(2), 140-140, 2015
NAID 130005108649

皮膚T細胞リンパ腫治療におけるvorinostatの役割

血液内科 68(1), 134-138, 2014-01
NAID 40019971895

多発性骨髄腫のこれまでの治療と最近の治療について

東京女子医科大学雑誌 83(E2), E476-E484, 2013-03-31
NAID 110009575055

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Vorinostat
Systematic (IUPAC) name
	N-hydroxy-N'-phenyl-octanediamide
Clinical data
Trade names	Zolinza
AHFS/Drugs.com	monograph
MedlinePlus	a607050
Licence data	US FDA:link
Pregnancy cat.	D (US)
Legal status	℞-only (US)
Routes	Oral
Pharmacokinetic data
Protein binding	71%
Metabolism	Hepatic glucuronidation and oxidation; CYP system not involved
Half-life	2 hours
Excretion	Renal (negligible)
Identifiers
CAS number	149647-78-9
ATC code	L01XX38
PubChem	CID 5311
DrugBank	DB02546
ChemSpider	5120
UNII	58IFB293JI
KEGG	D06320
ChEMBL	CHEMBL98
Chemical data
Formula	C14H20N2O3
Mol. mass	264.32 g/mol
	SMILES O=C(Nc1ccccc1)CCCCCCC(=O)NO;
	InChI InChI=1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18) ; Key:WAEXFXRVDQXREF-UHFFFAOYSA-N ;
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英: vorinostat
商: ゾリンザ
関: その他の腫瘍用薬

抗悪性腫瘍薬;ヒストン脱アセチル化酵素阻害作用

[1] "ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration" (Press release). Merck & Co.. June 7, 2006. http://www.merck.com/newsroom/press_releases/research_and_development/2006_0607.html. Retrieved 2006-10-06.

[2] HDAC Inhibitors Base (vorinostat)

[3] "FDA Approves New Drug for Skin Cancer, Zolinza" (Press release). Food and Drug Administration. October 6, 2006. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108758.htm. Retrieved 2006-10-06.

[Richon-4] Richon, Victoria. "Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor". British Journal of Cancer. http://www.nature.com/bjc/journal/v95/n1s/full/6603463a.html. Retrieved 3 May 2012.

[atlas-5] Cuneo A, Castoldi. "Mycosis fungoides/Sezary's syndrome". http://atlasgeneticsoncology.org/Anomalies/MycosFungID2039.html. Retrieved 2008-02-15.

[6] "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. http://www.eurekalert.org/pub_releases/2007-06/mc-vsa053007.php. Retrieved 2007-06-03.

[7] ttp://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html Dec 2009. URL dead Jan 2012

[8] "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)". http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/.

[9] "Study of the Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART". ClinicalTrials.gov. 2011-03-21. http://www.clinicaltrials.gov/ct2/show/NCT01319383.

[pmid19239360-10] Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM (2009). "Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid.". AIDS Res Hum Retroviruses 25 (2): 207–12. doi:10.1089/aid.2008.0191. PMC 2853863. PMID 19239360. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2853863/.

[pmid19136668-11] Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J et al. (2009). "Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells.". J Biol Chem 284 (11): 6782–9. doi:10.1074/jbc.M807898200. PMC 2652322. PMID 19136668. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2652322/.

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vorinostat