Development of vorinostat: current applications and future perspectives for cancer therapy.
Vorinostat is a potent histone deacetylase inhibitor that blocks the catalytic site of these enzymes. A large number of cellular proteins are modified post-translationally by acetylation, leading to altered structure and/or function. Many of these proteins, such as core nucleosomal histones and transcription factors, function in key cellular processes and signal transduction pathways that regulate cell growth, migration, and differentiation. At concentrations that are non-toxic to normal cells, vorinostat dramatically alters cellular acetylation patterns and causes growth arrest and death and in a wide range of transformed cells, both in vitro and in animal tumor models. Vorinostat has shown promising clinical activity against hematologic and solid tumors at doses that have been well tolerated by patients. Recent non-clinical experiments that explored the effects of vorinostat in combination with other chemotherapeutic agents have begun to illuminate potential mechanisms of action for this histone deacetylase inhibitor and are providing guidance for new avenues of clinical investigation.
Richon
Victoria M
VM
Merck Research Laboratories, Boston, MA, United States.
Garcia-Vargas
Jose
J
Hardwick
James S
JS
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D000077337:Vorinostat
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011838:Radiation-Sensitizing Agents; D000077337:Vorinostat; D015254:DNA Modification Methylases; D006655:Histone Deacetylases