Histone Deacetylase Inhibitors

FDA-Approved Drugs: Vorinostat (Zolinza, suberoylanilide hydroxamic acid [SAHA])

Investigational Drugs: CRA-024781 (Celera Genomics), depsipeptide (Romidepsin)

Mechanism of Action

DNA coils around histones, which are proteins that help push the DNA strands into tightly coiled chromatin in the nucleus of the cell. Histones play an important role in turning genes on and off. When the chromatin is loose and uncoiled, the gene is turned on and DNA transcription can occur. If there is too much deacetylation of the histones (caused by an overexpression of histone deacetylase), such as may occur in cancer, the chromatin is tightly coiled and closed, so that the gene is turned off (cannot be transcribed). Deacetylation is the removal of acetyl groups from proteins or transcription factors. For example, if the gene that is silenced is a tumor suppressor gene, then without the "brakes" on cell division, cancer cells may proliferate. Another gene that may be silenced is a cyclin kinase inhibitor, which regulates the cell cycle. Again, the tumor would be able to continue to divide and make more tumor cells. Imagine a Slinky toy as a DNA coiled helix. When you move it so that the rings are open, you see that the portion of DNA that codes for the gene is exposed. When the rings are open, the gene can be activated and transcribed. When the Slinky moves down a step, it closes in on itself, and there is no way that the gene can be exposed for transcription. Vorinostat is a histone deacetylase (HDAC) inhibitor, which blocks the deacetylase enzyme and allows the acetyl groups to accumulate on the histones. This uncoils the DNA within the chromatin so that genes are exposed; they become activated and are then transcribed. This causes cancer cells to stop dividing (cell cycle arrest) and to die (apoptosis).

Vorinostat Metabolism

The drug is well absorbed, and if taken with a high-fat meal had a 33% higher extent of absorption and a slightly slower rate of absorption (not clinically significant). The drug is primarily metabolized by glucuronidation and hydrolysis, followed by oxidation into two inactive metabolites. Less than 1% of the drug is recoverable in the urine.

Indications

Vorinostat is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent, or recurrent disease during or after two systemic therapies.

Patient Education

Educate the patient about the correct oral administration of vorinostat: swallow the prescribed capsules (400 mg) whole (do not chew or break), once a day with food. Drink at least eight 8-ounce glasses of liquid a day.

• Blood tests, including blood sugar, will be checked every 2 weeks for the first 2 months of therapy, and then monthly. If the patient has diabetes, tell the patient that hyperglycemia may occur and he should monitor his blood sugar closely.

• Teach the patient how to self-administer prescribed antiemetic and antidiarrheal agents, and to report nausea/vomiting or diarrhea (that is unrelieved in 24 hours) right away.

• Teach the patient to report any bleeding, as dose- related thrombocytopenia may occur.

• If the patient develops intolerance, teach him how to take the prescribed reduced dose (300 mg every day, or 300 mg for 5 days every week if the 300 mg dose is not well tolerated).

• Teach the patient to come to the emergency department right away if he develops pain in the calf of the leg or the chest, or develops difficulty breathing.

• Drug is fetotoxic; teach the patient to use effective birth control measures.

Interactions

Vorinostat has interactions with the following:

• Warfarin and other coumarin-derivative anticoagulants: causes prolonged prothrombin time (PT) and international normalized ratio (INR) when taken concomitantly. Monitor the PT or INR closely when taken together.

• Valproic acid and other HDAC inhibitors: increased toxicity (severe thrombocytopenia, gastrointestinal bleeding) when combined; if used together, monitor platelet count every 2 weeks for the first 2 months.

Special Considerations

• Monitor blood cell/platelet counts and chemistries (electrolytes including potassium, magnesium, calcium; glucose; serum creatinine) every 2 weeks during the first 2 months of therapy, then every month. Evaluate electrocardiogram (ECG), including QTc interval, at baseline and periodically during therapy.

• Drug may cause hyperglycemia, requiring close monitoring of serum glucose, especially in patients with a history of diabetes or hyperglycemia. Diet and/or glycemic-lowering-agent dose may need to be adjusted.

• Vorinostat may cause prolongation of the QTc interval on ECG. Electrolyte serum level, ECG should be assessed at baseline, and regularly during treatment. Use the drug cautiously in patients with prolonged QTc intervals. Replete potassium and magnesium as needed to keep serum levels within normal limits.

• Use cautiously in patients with hepatic impairment and monitor closely for side effects.

• Pulmonary embolism and deep vein thrombosis may occur rarely.