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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1401-1408
Depsipeptide (FR901228): A Novel Therapeutic Agent With Selective, In
Vitro Activity Against Human B-Cell Chronic Lymphocytic Leukemia Cells
John C. Byrd,
Charlotte Shinn,
Rajani Ravi,
Carl R. Willis,
Jamie
K. Waselenko,
Ian W. Flinn,
Nancy A. Dawson, and
Michael R. Grever
From the Division of Hematology-Oncology, Walter Reed Army Medical
Center, Washington, DC; the Department of Medicine, Uniformed Services
University of Health Sciences, Bethesda, MD; and the Division of
Hematologic Malignancies, Johns Hopkins Oncology Center, Baltimore, MD.
Therapy of B-cell chronic lymphocytic leukemia (CLL) has been
limited by both the nonselectivity of therapeutic agents toward normal
residual immune cells and inherent drug resistance. Identification of
agents that spare normal immune effector cells, thus facilitating addition of immune-based therapies, 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 µmol/L,
respectively. Depsipeptide had marked selective cytotoxicity when
compared with normal blood mononuclear cells, in which the
LC50 was 3.44 µmol/L at 4 hours (P = .03), 0.965 µmol/L at 24 hours (P = .01), and 0.0318 µmol/L at
96 hours (P = .04). Inhibition of bone marrow progenitor cell
growth was also minimal after incubation with 0.015 µmol/L (19%
inhibition of colony forming unit-granulocyte-macrophage [CFU-GM];
17% inhibition burst forming unit-erythroid [BFU-E]) and 3.44 µmol/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 proteins after depsipeptide exposure (0.015 µmol/L) included no change in bcl-2, elevation of bax, and decreased
expression of p27. These data demonstrate that depsipeptide has
significant selective in vitro activity against human CLL cells
concurrent with favorable alterations of the bcl-2:bax protein ratio
and decrease in p27 expression. Such findings strongly support the early introduction of depsipeptide into clinical trials for patients with CLL.
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