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ZOLINZA^® (vorinostat) An Oral Histone Deacetylase (HDAC) Inhibitor
The Flash video presentation is an artistic representation of the mechanisms of action of ZOLINZA.

ZOLINZA^® (vorinostat) is an oral histone deacetylase, or HDAC, inhibitor. HDAC is an enzyme that plays a key role in chromatin remodeling and the epigenetic process involved in the regulation of gene expression. Epigenetics refers to the heritable modifications in gene function or activity without changes in the DNA sequence. Epigenetic processes are genetic modifications that affect gene regulation by changing the DNA conformation. Epigenetic changes are found in many different cancer cell types. One such change is histone modification that may be caused by over expression or aberrant recruitment of HDACs.

Within the chromosome, DNA is packaged into chromatin. Chromatin consists of DNA, structural histone proteins, and nonhistone proteins. Within chromatin, the repeating unit is the nucleosome. Nucleosomes are made up of 146 base pairs of 2 superhelical turns of DNA wrapped around a core of 8 histones. The histones are responsible for maintaining the chromatins shape and structure. There are 4 types of histones: H2A, H2B, H3, and H4.

Epigenetic modifications, such as histone acetylation, occur at the aminoterminal tails of the histones that protrude from the nucleosomes. Acetylation of histones is generally acknowledged to play a key role in the regulation of gene expression. Histone acetylation is controlled by the balance and the activity of 2 enzymes: histone acetyltransferase, or HAT, and histone deacetylase, or HDAC.

For a gene to be transcribed, it must become physically accessible to transcriptional machinery. Acetylation of histones by HAT causes uncoiling of DNA and an open chromatin structure. This causes genes to become accessible to transcription factors, allowing gene expression to occur and proteins to be made.

Conversely, deacetylation of histones by HDAC results in tight coiling of the DNA and a closed chromatin structure. In some cancer cells, there is an over expression of HDACs and aberrant recruitment of HDACs or an under expression of HATs, resulting in hypoacetylation of histones and therefore a condensed or closed chromatin structure.

The closed chromatin may prevent access of the transcriptional machinery to the DNA, repressing gene expression. HDAC has also been found to deacetylate nonhistone proteins and transcription factor proteins that are involved in normal cell-cycle regulation. ZOLINZA, an HDAC inhibitor, inhibits the enzymatic activity of Class I histone deacetylases HDAC1, HDAC2, and HDAC3, and the Class II histone deacetylase HDAC6 at nanomolar concentrations, IC₅₀<86 nM.

HDAC inhibition allows for the accumulation of acetyl groups on the histones, resulting in uncoiling of DNA within chromatin, an open chromatin structure, and transcriptional activation of genes.

As shown by in vitro studies, ZOLINZA induces cell-cycle arrest and can also cause apoptosis in some transformed cells. The mechanism of the antineoplastic effect of ZOLINZA has not been fully characterized.

ZOLINZA is an oral HDAC inhibitor with proven efficacy and durable response in patients with advanced cutaneous T-cell lymphoma. ZOLINZA is a histone deacetylase (HDAC) inhibitor indicated for treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following 2 systemic therapies.

Selected Important Safety Information

• Pulmonary embolism and deep vein thrombosis have been reported. Monitor patients for pertinent signs and symptoms, particularly in patients with a history of thromboembolic events.
• Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. If platelet counts and/or hemoglobin are reduced during treatment, modify the dose or discontinue therapy.
• Gastrointestinal (GI) disturbances (eg, nausea, vomiting, and diarrhea) may require antiemetics, antidiarrheals, and fluid and electrolyte replacement to prevent dehydration. Adequately control preexisting GI disturbances before beginning therapy with ZOLINZA.
• Hyperglycemia has been observed. Monitor serum glucose, especially in diabetic or potentially diabetic patients. Adjustment of diet, therapy for increased glucose, or both may be necessary to prevent hyperglycemia.
• QTc prolongation has been observed. Monitor electrolytes and ECGs at baseline and periodically during treatment. Administer with caution in patients who have or may develop QTc prolongation. Hypokalemia or hypomagnesemia should be corrected before administering ZOLINZA.
• The most common adverse events observed in clinical trials with ZOLINZA, regardless of causality, were fatigue (52%), diarrhea (52%), nausea (41%), dysgeusia (28%), thrombocytopenia (26%), anorexia (24%), decreased weight (21%), and muscle spasms (20%).

Before prescribing ZOLINZA, please read the Prescribing Information.