Vorinostat

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Vorinostat
Clinical data
Pronunciation/vɒˈrɪnstæt/ vorr-IN-oh-stat
Trade namesZolinza
AHFS/Drugs.comMonograph
MedlinePlusa607050
License data
Routes of
administration
Oral (capsules)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
CYP system not involved
Metabolitesvorinostat O-glucuronide, 4-anilino-4-oxobutanoic acid (both inactive)[2]
Elimination half-life~2 hours (vorinostat and O-glucuronide), 11 hours (4-anilino-4-oxobutanoic acid)
ExcretionRenal (negligible)
Identifiers
  • N-Hydroxy-N'-phenyloctanediamide
JSmol)
  • O=C(Nc1ccccc1)CCCCCCC(=O)NO
  • 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) checkY
  • Key:WAEXFXRVDQXREF-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Vorinostat (

epigenetic
activities.

Vorinostat is marketed under the name Zolinza (

cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after two systemic therapies.[2][4] The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.[5][6]

Medical uses

Vorinostat was the first histone deacetylase inhibitor[7] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006.[8]

Development

In 1966, Charlotte Friend published her observation that a suspension of murine erythroleukemia cells underwent cytodifferentiation to normal erythrocytes when treated with dimethylsulfoxide (DMSO, a common drug solvent and cryoprotectant frequently used for cell culture freezing) at 280 mmolar.[9][10] Memorial Sloan-Kettering researcher Paul Marks approached Columbia University chemist Ronald Breslow about these findings and together they decided to develop more potent analogs of DMSO, in order to make use of this property for cancer treatment. Their optimization process lead to the discovery of suberoylanilide hydroxamic acid and its HDAC-inhibiting property.[6][11]

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.[12] 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.[12] It acts on class I, II and IV of histone deacetylase.

Clinical trials

Vorinostat has also been used to treat

Sézary syndrome, another type of lymphoma closely related to CTCL.[13]

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).[14]
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 carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival.[15]

It has given encouraging results in a phase II trial[16] for myelodysplastic syndromes in combination with idarubicin and cytarabine.[17] It failed to demonstrate efficacy in treating acute myeloid leukemia in an earlier phase II study.[18]

Preclinical investigations

Vorinostat is being investigated as a potential HIV latency reversing agent (LRA) as part of an investigational therapeutic strategy known as "shock and kill".[19] Vorinostat was shown to reactivate HIV in latently HIV-infected T cells, both in vitro and in vivo.[20][21]

Vorinostat also has shown some activity against the pathophysiological changes in

α1-antitrypsin deficiency[22] and cystic fibrosis.[23]
Recent evidence also suggests vorinostat can be a therapeutic tool for Niemann-Pick type C1 (NPC1), a rare lysosomal lipid storage disease.[24]

Preclinical experiments by University of Alabama at Birmingham researchers suggest the cancer drugs vorinostat, belinostat and panobinostat might be repurposed to treat infections caused by human papillomavirus, or HPV.[25]

See also

References

  1. ^ "Withdrawal Assessment Report for Vorinostat MSD 100 mg Hard Capsules (vorinostat)" (PDF). European Medicines Agency. 23 October 2008. p. 9. Retrieved 1 September 2016.
  2. ^ a b "Zolinza (vorinostat) Capsules. Full Prescribing Information" (PDF). Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Retrieved 1 September 2016.
  3. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 56" (PDF). WHO Drug Information. 20 (3): 232. 2006. Archived from the original (PDF) on July 5, 2011. Retrieved 1 September 2016.
  4. ^ "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. Archived from the original on September 14, 2006. Retrieved October 6, 2006.
  5. PMID 24023063
    .
  6. ^ .
  7. ^ "Vorinostat". HDAC Inhibitors Base.
  8. ^ "Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 16 February 2014.
  9. PMID 5923328
    .
  10. .
  11. . Retrieved 2022-11-18.
  12. ^ .
  13. ^ Castoldi G, Cuneo A (May 2005). "Mycosis fungoides/Sezary's syndrome". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-02-15.
  14. ^ "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. Retrieved 2007-06-03.
  15. PMID 19933908
    .
  16. .
  17. ^ Langholtz J, Haehle M (11 January 2012). "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)". The MDS Beacon. Archived from the original on 2014-10-30. Retrieved 2012-01-17.
  18. PMID 19794082
    .
  19. ^ Clinical trial number NCT01319383 for "The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART" at ClinicalTrials.gov
  20. PMID 19239360
    .
  21. .
  22. .
  23. .
  24. .
  25. ^ "Cancer drug may help treat human papillomavirus infections". ScienceDaily. 30 November 2018. Retrieved 2018-11-30.

External links