Impact of Prolonged Infusions of the Putative Differentiating Agent Sodium Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid Leukemia

摘要: The aromatic fatty acid sodium phenylbutyrate (PB) promotes cytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition histone deacetylase (HDAC) may account for many its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence clinical activity acute myeloid leukemia myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on vitro studies. Because prolonged exposure to suboptimal PB led changes similar more brief higher concentrations, feasibility administration was performed. Selected patients with syndrome treated as continuous i.v. infusion via ambulatory pump. Sequential cohorts 7 consecutive days out 14 or 21 28. Prolonged infusions well tolerated; dose-limiting central nervous system toxicity developed 1 23 treated. End-of-infusion maintained within range sufficient inhibit HDAC. Two 21/28 schedule hematological improvement. are making this an attractive platform investigation HDAC inhibition.