Effects of desferrioxamine on normal and leukemic human hematopoietic cell growth: in vitro and in vivo studies.
The iron chelator desferrioxamine (DFO) has been previously shown to be an S-phase inhibitor of cell proliferation. To investigate its potential as an antileukemic drug, we first studied the effects of DFO on the in vitro growth of normal human hematopoietic progenitors (CFU-GM and BFU-E) and clonogenic cells from human leukemic cell lines. Then we evaluated the effects of DFO on progression of leukemia refractory to conventional therapy in two individuals. Micromolar concentrations of DFO determined a dose-dependent inhibition of normal progenitor growth, with inhibitory dose 50% (ID50) for CFU-GM and BFU-E being 6.7 and 5.5 microM/liter, respectively. Marked inhibitory effects were observed on clonogenic cells from HL-60 (ID50 = 1.4 microM/liter) and U-937 (ID50 = 3.6 microM/liter) human leukemic cell lines grown in semisolid medium. When DFO was given intravenously to a patient with lymphoid blast crisis of chronic myelogenous leukemia, a marked reduction in circulating blast count was observed. On the contrary, no in vivo effect was observed in a patient with acute nonlymphocytic leukemia having transfusional iron overload. We conclude that: (a) DFO is an inhibitor of both normal and leukemic myeloid cell proliferation in vitro; (b) our limited in vivo observations and a previous case study suggest that intravenous administration of DFO to patients with normal to low plasma iron may result in leukemic cytoreduction in vivo.
Dezza
L
L
Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, Italy.
Cazzola
M
M
Danova
M
M
Carlo-Stella
C
C
Bergamaschi
G
G
Brugnatelli
S
S
Invernizzi
R
R
Mazzini
G
G
Riccardi
A
A
Ascari
E
E
D000754:Anemia, Refractory, with Excess of Blasts / Q000188:drug therapy; D001752:Blast Crisis; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003676:Deferoxamine / Q000494:pharmacology* / Q000627:therapeutic use*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D014411:Neoplastic Stem Cells / Q000166:cytology*
D003676:Deferoxamine