Depsipeptide (FR901228): A novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells

Therapy of B-cell chronic lymphocytic leukemia (CLL) has been limited by bo th the nonselectivity of therapeutic agents toward normal residual immune c ells and inherent drug resistance. Identification of agents that spare norm al immune effector cells, thus facilitating addition of immune-based therap ies, and that modulate factors associated with drug resistance in CLL might represent a major therapeutic advance, Depsipeptide (FR901228) is a novel agent entering clinical trials that has selective in vitro activity against resistant leukemia cell lines. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 10) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at depsipeptide concentrations of 0.038, 0.024, and 0.015 mu mol/L, respectively. Depsipeptide had marked sel ective cytotoxicity when compared with normal blood mononuclear cells, in w hich the LC50 was 3.44 mu mol/L at 4 hours (P = .03), 0.965 mu mol/L at 24 hours (P = .01), and 0.0318 mu mol/L at 96 hours (P = .04), Inhibition of b one marrow progenitor cell growth was also minimal after incubation with 0. 015 mu mol/L (19% inhibition of colony forming unit-granulocyte-macrophage [CFU-GM]; 17% inhibition burst forming unit-erythroid [BFU-E]) and 3.44 mu mol/L (24% inhibition of CFU-GM; 57% inhibition BFU-E) of depsipeptide for 4 hours, followed by a 14-day incubation period. Expression of apoptotic pr oteins after depsipeptide exposure (0.015 mu mol/L) included no change in b cl-2, elevation of bax, and decreased expression of p27. These data demonst rate that depsipeptide has significant selective in vitro activity against human CLL cells concurrent with favorable alterations of the bcl-2:bax prot ein ratio and decrease in p27 expression. Such findings strongly support th e early introduction of depsipeptide into clinical trials for patients with CLL. (C) 1999 by The American Society of Hematology.