Vorinostat is marketed under the nameZolinza (/zoʊˈlɪnzə/zoh-LIN-zə) byMerck for the treatment of cutaneous manifestations in patients withcutaneous 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 chemistRonald Breslow and Memorial Sloan-Kettering researcherPaul Marks.[5][6]
In 1966,Charlotte Friend published her observation that a suspension of murineerythroleukemia cells underwent cytodifferentiation to normal erythrocytes when treated withdimethylsulfoxide (DMSO, a common drug solvent andcryoprotectant frequently used forcell culture freezing) at 280 mmolar.[9][10] Memorial Sloan-Kettering researcherPaul Marks approached Columbia University chemistRonald 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]
Vorinostat has been shown to bind to the active site ofhistone 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.
Vorinostat has also been used to treatSézary syndrome, another type of lymphoma closely related to CTCL.[13]
A recent study suggested that vorinostat also possesses some activity against recurrentglioblastoma 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 advancednon-small-cell lung carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival.[15]
Vorinostat is being investigated as a potentialHIV 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-infectedT cells, bothin vitro andin vivo.[20][21]
Preclinical experiments by University of Alabama at Birmingham researchers suggest the cancer drugs vorinostat,belinostat andpanobinostat might be repurposed to treat infections caused byhuman papillomavirus, or HPV.[25]
^abMarks PA, Breslow R (January 2007). "Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug".Nature Biotechnology.25 (1):84–90.doi:10.1038/nbt1272.PMID17211407.S2CID12656582.
^Friend C, Patuleia MC, De Harven E (September 1966). "Erythrocytic maturation in vitro of murine (Friend) virus-induced leukemic cells".National Cancer Institute Monograph.22:505–522.PMID5923328.
^Castoldi G, Cuneo A (May 2005)."Mycosis fungoides/Sezary's syndrome".Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved2008-02-15.
^Clinical trial numberNCT01319383 for "The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART" atClinicalTrials.gov
^Alam MS, Getz M, Haldar K (February 2016). "Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model".Science Translational Medicine.8 (326): 326ra23.doi:10.1126/scitranslmed.aad9407.PMID26888431.S2CID5762569.
N
Y (what is this?) (verify)