Vorinostat-An Overview.

Vorinostat is a new drug used in the management of cutaneous T cell lymphoma when the disease persists, gets worse or comes back during or after treatment with other medicines. It is an efficacious and well tolerated drug and has been considered a novel drug in the treatment of this condition. Currently apart from cutaneous T cell lymphoma the role of Vorinostat for other types of cancers is being investigated both as mono-therapy and combination therapy.

What was known?

Vorinostat is a histone deacetylase inhibitor.

It is an FDA approved drug for the treatment of cutaneous T cell lymphoma.

Introduction

Vorinostat is a histone deacetylase (HDAC) inhibitor, structurally belonging to the hydroxymate group. Other drugs in this group include Givinostat, Abexinostat, Panobinostat, Belinostat and Trichostatin A. These are an emergency class of drugs with potential anti-neoplastic activity. These drugs were developed with the realization that apart from genetic mutation, alteration of HDAC enzymes affected the phenotypic and genotypic expression in cells, which in turn lead to disturbed homeostasis and neoplastic growth. HDAC inhibitors have multiple effects in vivo and in vitro specific for cell types, like arresting growth, affecting cell differentiation and bringing about complete apoptosis of malignant cells. These drugs can be used both as mono-therapy and in combination with other anti-neoplastic drugs. Despite the proven anti-cancer effects of HDAC inhibitors many aspects of its mechanics are not fully clear. This review will help us understand about these drugs in particular Vorinostat which is an FDA-approved drug for cutaneous T-cell lymphoma (CTCL).

Chemistry

Vorinostat also known as suberoylanilide hydroxamic acid (SAHA) is an orally bioavailable inhibitor of class I and II HDACs. It is a small-molecular-weight linear hydroxamic acid compound, with an empirical formula of C14H20N2O3 and a molecular weight of 264.32 g/mol.[1] The pKa of Vorinostat is approximately 9. Vorinostat is slightly soluble in water, alcohol, isopropanol and acetone and is completely soluble in dimethyl sulfoxide.

Mechanism of action

Vorinostat is a broad inhibitor of HDAC activity and inhibits class I and class II HDAC enzymes.[23] However, Vorinostat does not inhibit HDACs belonging to class III. Based on crystallographic studies, it has been seen that Vorinostat binds to the zinc atom of the catalytic site of the HDAC enzyme with the phenyl ring of Vorinostat projecting out of the catalytic domain onto the surface of the HDAC enzyme.[4] On binding to the HDAC enzyme there is accumulation of acetylated proteins including histones, which in turn manifests in multiple cellular effects.[56] The effects seen include transcriptional and non-transcriptional.[78]

Transcriptional effects

The transcriptional effects could be by the direct HDAC binding of Vorinostat or indirectly by acting on various transcriptional factors like E2F-1, YY-1, Smad 7, p 53, Bcl-6 and GATA-1. This may result in the alteration in the expression of certain genes. For example, acetylation of Bcl-6 transcriptional activator can give rise to an inhibition of transcriptional repression by Bcl-6.[9] Other indirect transcriptional effects seen with Vorinostat are acetylation of lysine residues of alpha tubulin and heat shock protein-90. This in turn may lead to decreases in the activity of pro-growth and pro-survival client proteins, such as Bcr-Abl, mutant FLT-3, c-raf and AKT in human leukemia cells.[10]

Non-transcriptional effects

The non-transcriptional effects of Vorinostat can be divided into:

Cell cycle arrest

Apoptosis

Inhibition of angiogenesis

Down regulation of immunosuppressive interleukins

Cell cycle arrest

Vorinostat up regulates cyclin-dependent kinase inhibitor p 21 which in turn antagonizes the cyclin/CDK complexes leading to cell G1 cycle arrest in malignant cell lines.[1112] Furthermore Vorinostat causes reduced cyclin-dependant kinase activity via down regulation of cyclins, causing Rb dephosphorylation and indirectly affecting E2F transcription activity.[13]

Apoptosis

Vorinostat induces apoptosis in hematological malignancies and solid tumors using both transcription- and transcription-independent mechanisms.[1415] Inhibition of HDAC changes the balance between pro and anti-apoptotic proteins involved in cell death. Extrinsic apoptotic pathways, death receptors and ligands are in turn up regulated by Vorinostat. Furthermore, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is restored by Vorinostat in TRAIL-resistant malignant cells.[16] Along with this Vorinostat down regulates pro-survival proteins like Bcl-1 and Bcl-2 which regulate mitochondrial integrity,[17] and up regulate pro-apoptotic proteins such as Bim, Bak and Bax, which function as sensors of cellular stress and initiate the intrinsic pathway.[18] Apart from this, hyperacetylation in malignant cells promotes stabilization of p 53[19] which is of importance in CTCL lines.[20]

Inhibition of angiogenesis

Vorinostat acts indirectly under hypoxic conditions suppressing hypoxia inducible factor (HIF)-1 alpha and vascular endothelial growth factor (VEGF) and thus blocks angiogenesis.[2122]

Down regulation of immunosuppressive interleukins

Vorinostat down regulates interleukin 10(IL-10), an immunosuppressive interleukin and increases IL-2 and IL-4 RNA, supporting the fact that Vorinostat acts as a STAT 3 inhibitor.[23]

Vorinostat is toxic selectively on tumor cells. The reason for the selective toxicity of Vorinostat is not fully understood. However, studies have shown that thioredoxin in normal cells may be responsible for preventing the insult on the normal cells. Recent studies have also shown that HR23B is a bio-marker for the sensitivity of CTCL cells to Vorinostat.[24]

Pharmacokinetics

Vorinostat administered orally in a dose of 200-600 mg has demonstrated a linear relationship between the plasma concentration and Vorinostat dose.[25] The t1/2 of Vorinostat is around 60 to 100 minutes. The absorption and bioavailability of Vorinostat do not significantly differ in the absence or presence of food, although administering Vorinostat with food may prevent some gastro-intestinal side effects. Vorinostat is metabolized and excreted after glucoronidation by uridine diphosphate glucoronosyl transferase (UGT). Polymorphism in the gene encoding this enzyme system, UGT1A1, maybe an important predictor of Vorinostat toxicity and response levels in individual patients.[26] Similarly certain polymorphisms in the thymidylate synthase gene may predict whether Vorinostat will generate an efficacious response.[27] Vorinostat is not metabolized by and does not inhibit cytochrome P-450 isoenzyme system and only two drugs, warfarin and sodium valproate, have been noted to interact with Vorinostat.[28]

Indications

Vorinostat is an FDA-approved drug in the management of CTCL. Studies have also shown that Vorinostat may inhibit tumor growth by both oral and parenteral administration in prostate cancer,[29] leukemia,[30] breast cancer,[31] glioma[32] and lung cancer.[33]

Dosing

The approved dosage of Vorinostat is 400 mg given orally once a day.[34] With this dosage a response rate of 31% is seen with very few life-threatening adverse effects. However, if adverse effects become intolerable a reduction of the dosage to 300 mg once daily can be warranted. In patients who received Vorinostat 300 mg twice daily produced an overall response rate of only 21% with adverse effects like pulmonary embolism and thrombocytopenia. Vorinostat is supplied as 100 mg capsules approved for oral administration. However, an i.v. formulation has been comparatively analyzed for efficacy and safety.[35] Response rates for i.v. Vorinostat 300-600 mg/m2 given 5 days a week for 3 weeks were similar to the oral dosing of 400 mg per day. However, severe hematologic adverse effects were quite common in the patients who received i.v. Vorinostat. Secondly, the inconvenience of daily infusion render the oral route better suited for CTCL treatment. Prior to starting Vorinostat various other skin directed therapies and cytotoxic therapies ought to be considered in patients with systemic and progressive disease.[36]

Adverse effects

Toxicities with Vorinostat were seen when the dosing exceeded 400 mg a day, rendering the clinical benefits of dose escalation very minimal. With the FDA-approved dosing the most common side effects encountered include fatigue, diarrhea and nausea. These side effects were usually mild to moderate needing no intervention or non-invasive intervention. Other side effects that were life threatening and required hospitalization included thrombocytopenia, dehydration,[37] pulmonary embolism, squamous cell carcinoma and severe anemia. There have also been reports of QTc-interval prolongation in some patients taking Vorinostat.[38] Therefore, it is advisable that patients who are on anti-arrhythmic drugs should undergo a regular screening when on Vorinostat. Vorinostat is a category D drug in pregnancy. A study in animals found that Vorinostat crosses the placenta and may harm the developing fetus.[39] The most common developmental defects seen were low fetal birth weight and incomplete ossification of the skull, vertebrae, and other bones of the axial skeleton.

Future direction

In addition to its efficacy in CTCL Vorinostat appears to have activity in the treatment of other cancers. Multiple Phase I studies of Vorinostat for various solid and hematologic malignancies have shown promise. Studies have shown that Vorinostat had shown to give a complete response in a patient with diffuse large B-cell lymphoma (DLBCL), with partial responses in mesothelioma, laryngeal and thyroid tumors. Currently over 90 clinical trials involving Vorinostat are in progress. Results from some of these may provide insight into the efficacy of Vorinostat as monotherapy or as a part of combination therapy in various cancers.

Conclusion

Vorinostat, a novel HDAC inhibitor, is efficacious and well tolerated in patients with CTCL and is being investigated for its efficacy and safety in other types of cancers as a part of combination therapy.

What is new?

The efficacy of Vorinostat for prostate cancer, leukemia, breast cancer, glioma and lung cancer has been clearly demonstrated in the recent past.

At present various phase I trials for other solid and haematologic malignancies have shown promise with Vorinosta.