Vorinostat

BeschreibungVorinostat is the first drug in a new class of anti-cancer agents that inhibit histone deacetylases (HDAC). It was launched as an oral treatment for cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. HDACs are enzymes that catalyze the removal of the acetyl modification on lysine residues of proteins, including the core nucleosomal histones. Together with their counterpart histone acetyltransferases (HATs), HDACs regulate the acetylation level of the histones, which plays an important role in the regulation of chromatin plasticity and gene transcription. Hypoacetylation of histones is associated with a condensed chromatin structure resulting in the repression of gene transcription, whereas acetylated histones are associated with a more open chromatin structure and activation of transcription. In some cancer cells, there is an overexpression of HDACs, resulting in hypoacetylation of histones. Inhibitors of HDAC are thought to transcriptionally reactivate dormant tumor-suppressor genes by allowing for the accumulation of acetyl groups on histones and an open chromatin structure. Vorinostat inhibits the enzymatic activity of HDAC1, HDAC2, HDAC3, and HDAC6 at nanomolar concentrations (IC50 ＜86 nM). In vitro, it induces growth arrest, differentiation or apoptosis in a variety of tumor cells. In addition, vorinostat inhibits tumor growth in animal models bearing solid tumors, including breast, prostate, lung and gastric cancers, as well as hematologic malignancies such as multiple myeloma and leukemias.

VerwendenVorinostat, a histone deacetylase (HDAC) inhibitor from Merck, was approved for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma. Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3 and HDAC6 at nanomolar concentrations. HDAC inhibitors are potent differentiating agents toward a variety of neoplasms, including leukemia and breast and prostate cancers.