Suberoylanilide Hydroxamic Acid Vorinostat

Much work in breast cancer is focused on suberoylanilide hydroxamic acid (SAHA), a small molecule that binds to the catalytic site of HDACs, preventing them from interacting with its substrate. SAHA targets class I and II HDACs. SAHA affects transcription of cell-cycle regulators as well as other specific tran-scriptional programs and also has nontranscriptional cellular effects that are not HDAC-mediated. It promotes cell differentiation, cell cycle arrest, and apoptosis and induces histone acetylation. In breast cancer cell lines, SAHA inhibits clono-genic growth by inducing G1 and G2/M cell cycle arrest and apoptosis (26). Effects are seen within 24 to 72 hours following drug administration. Importantly, SAHA induces morphological changes consistent with differentiation in tumor cells with different properties, such as the ER-negative or HER2/neu or EGFR-amplified cell lines. In the MCF-7 cell line, SAHA enhances the activity of cytotoxic agents, such as cisplatin, epirubicin, paclitaxel, and docetaxel (27,28).

SAHA has been investigated in phase I clinical trials in hematological and non-hematological malignancies. The most common toxicities include fatigue, gastrointestinal symptoms, hyperglycemia, hypokalemia, anemia, and thrombocytopenia (29,30). Doses and schedules recommended for phase II studies include 300 mg po bid daily for 3 days a week, 400 mg po daily continuous, or 200 mg po bid daily continuous. The SAHA-related adverse events are generally rapidly reversible after study drug cessation. Inhibition of HDAC activity was achieved in peripheral blood mononuclear cells at the 200 mg dose level. At dose levels of 400 and 600 mg, the duration of HDAC inhibition lasted 10 or more hours. Tumor responses have been documented in patients with diffuse large B-cell lymphoma, laryngeal cancer, thyroid cancer, and mesothelioma. The FDA has recently approved SAHA (Zolinza, Mesck & Co., Inc.) for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies.

Several phase II studies of SAHA are ongoing in breast and other solid malignancies. Other studies are designed to understand modulation in breast cancer tissue. For example, in one study, women with primary breast cancer receive short-term administration of SAHA prior to definitive breast surgery, and baseline and change in markers of proliferation, apoptosis, as well as modulation of gene methylation and histone acetylation are evaluated. In addition, phase I and II clinical trials under investigation include combination therapy of SAHA and cytotoxic agents, biologic modulators, such as trastuzumab, bevacizumab, and novel agents. Other HDAC inhibitors have shown preliminary activity in the clinic, but an urgent need remains to identify optimal dose, schedule and duration of therapy for future clinical trials.

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