Alvocidib (flavopiridol) Vorinostat (Zolinza)

Vorinostat (Zolinza)

Vorinostat is a histone deacetylase inhibitor.  The chemical name for Vorinostat is suberoylanilide hydroxamic acid (SAHA).  Dr. Gary Schwartz discusses the rationale for this drug in his piece The Cell Cycle As A Drug Target.

Zolinza was approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma on October 6, 2006, and it is manufactured by Patheon, Inc., in Mississauga, Ontario, Canada, for Merck & Co., Inc.

Definition from the NCI Drug Dictionary:  Vorinostat is a synthetic hydroxamic acid derivative with antineoplastic activity. Vorinostat, a second generation polar-planar compound, binds to the catalytic domain of the histone deacetylases (HDACs). This allows the hydroxamic moiety to chelate zinc ion located in the catalytic pockets of HDAC, thereby inhibiting deacetylation and leading to an accumulation of both hyperacetylated histones and transcription factors. Hyperacetylation of histone proteins results in the upregulation of the cyclin-dependant kinase p21, followed by G1 arrest. Hyperacetylation of non-histone proteins such as tumor suppressor p53, alpha tubulin, and heat-shock protein 90 produces additional anti-proliferative effects. This agent also induces apoptosis and sensitizes tumor cells to cell death processes. Vorinostat crosses the blood-brain barrier.

Vorinostat is in numerous clinical trials.  Those most relevant to GIST include the following:

Phase I Study of Vorinostat (SAHA) and Bortezomib in Patients With Metastatic or Unresectable Solid Tumors NCT00227513

Phase I Study of Vorinostat (SAHA) in Combination With Flavopiridol in Patients With Advanced Solid Tumors
NCT00324480 

Phase I Study of Vorinostat (SAHA) in Patients With Metastatic or Unresectable Solid Tumors or Lymphoma and Hepatic Dysfunction
NCT00499811
 
Phase I Vorinostat + Sorafenib in Patients With Advanced Solid Tumors
NCT00635791