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VORINOSTAT: A HYDROXAMIC ACID

by Selleckchem | Sep 10 2012

VORINOSTAT OR SAHA (SUBEROYLANILIDE HYDROXAMIC ACID):
Histone deacetylase inhibitors or HDACi perform functions in the regulation of gene expression, cell cycle arrest, apoptosis stimulation in cancer cells and variation of different pathways in cancer cells such as cellular proliferation due to hyperacetylating the histone proteins. HDAC inhibitors are one of the leading approach for the treatment of cancers and tumors and among these inhibitors Vorinostat SAHA is the important one [1]. This inhibitor is found to have strong anti-oncogenic properties [2] and the Vorinostat structure contains a molecules having hydroxamic acid. For both classes of HDAC inhibitors that is class I and II the Vorinostat IC50 is about 50nM. The solubility of Vorinostat is around 2 mg/ml in ethanol where it is highly soluble in DMSO in which 65 mg/ml is Vorinostat solubility but it is poorly soluble in water. Stability of Vorinostat is of about 24 months when stored at -20 ºC. One can purchase Vorinostat for research purpose from any of the Vorinostat supplier by spending Vorinostat price that is $26 for a vial of 100mg however the prices are variably depending upon purity of the salt and supplier. Amongst different HDAC inhibitors the first FDA approved such inhibitor is Vorinostat HDAC inhibitor for the treatment of T-cell lymphoma [3].

PRECLINICAL STUDIES OF SAHA OR VORINOSTAT:
Vorinostat can also inhibit the both classes of HDAC enzymes that are class I and II, like many other HDAC inhibitors. The mechanism behind the apoptosis of cancerous cells by Vorinostat involves prolong H2AX foci which facilitates the apoptosis [4]. The cells of fibrosarcoma are also made more vulnerable to chemotherapy when treated with Vorinostat [5]. In a research report it is also found to inhibit the cell growth of pancreatic tumor cells [6]. Beyond the treatment of cancer Vorinostat is also having effective results against HIV in recent applications, in this case it induced the latent expression of HIV [7] in order to decompose latent HIV reservoir more quickly in patients treated with HAART [8].

CLINICAL TRIAL STUDIES OF VORINOSTAT:
Vorinostat is in clinical trials now due to a high performance in preclinical evaluations in in vitro and in vivo models it is also showing remarkable results in clinical studies. Vorinostat has been used alone against advanced tumor patients in clinical trials phase I [9] and also used in combination with other therapeutic agents [10]. In clinical phase II trials ovarian cancer was treated by Vorinostat and efficient results were observed [11]. In addition to this it has also been used against many other cancer types during phase II including metstatic breast cancer [12], Glioblastoma multiform [14] as well as in head and neck cancers [13].
During Vorinostat clinical trial the most remarkable success was about various leukemia and lymphoma cancers. In patients of NHL or Non-Hodgkin’s Lymphoma Vorinostat is a part of partial therapy in phase I of clinical studies [15] and the results of these studies inspired other researchers to use it for NHL treatment [16]. In phase II analysis mantle cell lymphoma was also studied with patients of NHL [17]. In clinical phase II trials B cell lymphoma was also treated with Vorinostat Zolinza chemotherapy and effective results were obtained [18]. In clinical phase IIb the chemotherapeutic potential of Vorinostat was also noted on patients with cutaneous T cell lymphoma [20] and in refractory CTCL [21]. In MM or multiple myeloma Vorinostat has proved its efficacy against this disease during phase I of clinical trials [22]. In myelodysplastic syndrome encouraging results were found when Vorinostat was used in phase I of clinical studies and it also enhanced the further research on leukemia [23].

REFERENCES:
1. Marks, P.A.a.B., R., Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotech, 2007.
2. Marks, P.A., Discovery and development of SAHA as an anticancer agent. Oncogene, 2007.
3. Duvic, M.V., J., Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opinion on Investigational Drugs, 2007.
4. Munshi, A.e.a., Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of γ-H2AX foci. Mol Cancer Ther, 2006.
5. Sampson, E.R.e.a., The histone deacetylase inhibitor vorinostat selectively sensitizes fibrosarcoma cells to chemotherapy. Journal of Orthopaedic Research, 2011.
6. Kumagai, T.e.a., Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. International Journal of Cancer, 2007.
7. Archin, N.M.e.a., Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses, 2009.
8. Contreras, X.e.a., Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem., 2009.
9. Kelly, W.K.e.a., Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer. Journal of Clinical Oncology, 2005.
10. Ramalingam, S.S.e.a., Phase I and Pharmacokinetic Study of Vorinostat, A Histone Deacetylase Inhibitor, in Combination with Carboplatin and Paclitaxel for Advanced Solid Malignancies. Clin Cancer Res, 2007.
11. Modesitt, S.C.e.a., A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study. Gynecologic Oncology, 2008.
12. Luu, T.H.e.a., A Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) in Metastatic Breast Cancer: A California Cancer Consortium Study. Clin Cancer Res, 2008.
13. Blumenschein, G.R.e.a., Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza™, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Investigational New Drugs, 2008.
14. Galanis, E.e.a., Phase II Trial of Vorinostat in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study. Journal of Clinical Oncology, 2008.
15. Stathis, A.e.a., Phase I Study of Decitabine in Combination with Vorinostat in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphomas. Clin Cancer Res, 2011.
16. Kirschbaum, M.H.e.a., A phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: Southwest Oncology Group Study S0517. Leukemia & Lymphoma, 2011.
17. Kirschbaum, M.e.a., Phase II Study of Vorinostat for Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma. Journal of Clinical Oncology, 2011.
18. Crump, M.e.a., Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Annals of Oncology, 2008.
19. Mann, B.S.e.a., Vorinostat for Treatment of Cutaneous Manifestations of Advanced Primary Cutaneous T-Cell Lymphoma. Clin Cancer Res, 2007.
20. Olsen, E.A.e.a., Phase IIB Multicenter Trial of Vorinostat in Patients With Persistent, Progressive, or Treatment Refractory Cutaneous T-Cell Lymphoma. Journal of Clinical Oncology, 2007.
21. Duvic, M.e.a., Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood, 2007.
22. Richardson, P.e.a., Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leukemia & Lymphoma, 2008.
23. Manero, G.G.e.a., Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood, 2008.