lithium-chloride and Leukemia--Myelomonocytic--Acute

Previous studies have demonstrated that combinations of all-trans retinoic acid (ATRA) with either granulocyte-colony stimulating factor (G-CSF) or lithium chloride (LiCl) produced synergistic terminal differentiation of WEHI-3B myelomonocytic leukemia (D(+)) cells. It was found that steady-state retinoic acid receptor alpha (RARalpha) protein levels were markedly reduced in these cells after exposure to ATRA. Because the presence of receptors for a hormone ligand is required for its action, differentiation therapy with ATRA may be self-limiting. The combination of G-CSF with ATRA significantly attenuated the loss of RARalpha protein, and synergistic terminal differentiation occurred. LiCl was more effective than G-CSF in preserving RARalpha pools and synergized with ATRA more strongly than G-CSF. These findings suggested that the prevention of RARalpha protein loss by G-CSF or LiCl in ATRA-treated cells functioned to extend the differentiation response to the retinoid and was responsible, at least in part, for the observed synergism. D(+) cells transfected with an expression plasmid containing RARalpha cDNA had a 6- to 8-fold increase in steady-state RARalpha mRNA compared with vector-transfected cells and showed a 2- to 3-fold increase in RARalpha protein. ATRA caused a reduction, but not a complete loss, of RARalpha protein in these transfectants, which were considerably more responsive than parental D(+) cells to ATRA as a single agent, supporting the concept that the protection of RARalpha pools results in a heightened differentiation response to ATRA.

Topics: Antineoplastic Agents; Cell Differentiation; Drug Synergism; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myelomonocytic, Acute; Lithium Chloride; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

The effects of LiCl on the proliferation of high proliferative potential colony-forming cells (HPP-CFC) and granulocyte macrophage colony-forming unit (CFU-GM) from bone marrow of BALB/c mice were observed. The colonies of HPP-CFC were supported by IL-1, IL-6, WEHI-3 conditioned medium (WEHI-3 CM, which contained IL-3) and L929 conditioned medium (L929-CM, which contained M-CSF); the colonies of CFU-GM were supported by WEHI-3 CM. It was shown that LiCl at concentrations ranging from 0.4 mmol/L to 2 mmol/L significantly inhibited the proliferation of HPP-CFC (P < 0.01), but concentrations ranging from 0.4 mmol/L to 1 mmol/L significantly increased the production of CFU-GM (P < 0.05), both effects displayed in dose-dependent manners. The different effects of LiCl on the proliferation of HPP-CFC and CFU-GM suggest that LiCl may induce HPP-CFC differentiation into more mature cells.

Topics: Animals; Cell Differentiation; Cell Division; Culture Media, Conditioned; Female; Hematologic Agents; Hematopoietic Stem Cells; Leukemia, Myelomonocytic, Acute; Lithium Chloride; Mice; Mice, Inbred BALB C; Tumor Cells, Cultured

The use of lithium chloride in manic-depressive patients and in patients receiving myelo-suppressive cancer chemotherapeutic agents is accompanied by a sustained leukocytosis due to an increase in granulocyte production. This property suggests that lithium chloride may have effects on hematopoietic differentiation. Treatment of cultured WEHI-3B D+ murine myelomonocytic and HL-60 human promyelocytic leukemia cells with millimolar concentrations of lithium chloride resulted in concentration-dependent increases in the number of differentiated myeloid cells, as determined by the ability of the cells to reduce nitroblue tetrazolium and by the binding of myeloid specific antibodies, and was associated with an inhibition of cellular proliferation. The effects of lithium chloride on growth and differentiation were antagonized by KCl, whereas NaCl had little effect. The induction of leukemic cell maturation by lithium chloride was markedly enhanced by the addition of low levels of retinoic acid. In contrast, other differentiation inducing agents (i.e. dimethyl sulfoxide and selenazofurin) had no effect on the degree of maturation induced by lithium. These findings suggest that the combination of lithium chloride and retinoic acid may have clinical utility in the treatment of leukemia through the induction of terminal differentiation.

Topics: Animals; Cell Differentiation; Chlorides; Growth Substances; Hematopoiesis; Humans; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Lithium; Lithium Chloride; Mice; Tretinoin; Tumor Cells, Cultured