cyclic-gmp and Leukemia--Myeloid

When the human myeloid leukemia cell line, K562, was induced to differentiate along the erythroid lineage by a 4 day treatment with 10 microM tiazofurin, the cellular content of diacylglycerol decreased to 35% of the value in untreated control cells. Under the same conditions the content of cGMP decreased to 61% of the control value. Tiazofurin inhibits guanine nucleotide biosynthesis and lowers cellular GTP. When guanosine and adenine were added together with tiazofurin, the differentiation of K562 was prevented, the concentration of diacylglycerol was maintained at control values, and the reduction in the concentration of cGMP was partially prevented. Other inducers of differentiation which acted by different mechanisms, caused similar changes in the concentrations of diacylglycerol and cGMP.

Topics: Antimetabolites, Antineoplastic; Cell Differentiation; Chromatography, DEAE-Cellulose; Cyclic GMP; Diglycerides; Glycerides; Hemoglobins; Humans; Leukemia, Myeloid; Protein Kinase C; Ribavirin; Tumor Cells, Cultured

Indoleamine 2,3-dioxygenase (IDO) is a flavin-dependent enzyme which uses superoxide anion as a cosubstrate to catalyze the decyclization of the pyrrole ring of L-tryptophan to form formylkynurenine. This enzyme is induced in some tumor cells after treatment with IFN-gamma. The mechanism of induction of IDO in tumor cells by IFN-gamma was studied in THP-1 human monocytic leukemia cells. Before the addition of IFN-gamma, no IDO could be detected in these cells. Treatment of THP-1 cells with IFN-gamma produced an induction of IDO, with peak activity occurring 72 to 96 h after addition of IFN-gamma. Because phorbol esters are known to induce many enzymes in cells, most likely through the activation of protein kinase C, the effects of PMA on the induction of IDO were determined. PMA potentiated the IFN-gamma-induced elevation of IDO, but by itself, was unable to induce enzyme activity. Maximum induction of IDO in the presence of PMA and IFN-gamma was obtained by preexposure of the cells to PMA for 48 h before the addition of IFN-gamma. Maximum induction of IDO after the addition of IFN-gamma occurred 24 to 48 h after addition of the cytokine to the culture medium. However, the induction of IDO does not appear to be potentiated through the activation of protein kinase C, because the addition of the protein kinase C inhibitor H-7 had no effect on the induction of IDO when the cells were exposed to PMA and IFN-gamma. Moreover, diacylglycerol was unable to replace PMA in these studies. Studies with cAMP and cGMP analogs suggest a role for these compounds in the regulation of IDO expression.

Topics: Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Induction; Humans; In Vitro Techniques; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon-gamma; Leukemia, Myeloid; Monocytes; Protein Kinase C; Tetradecanoylphorbol Acetate; Time Factors; Tryptophan Oxygenase; Tumor Cells, Cultured

Topics: Cells, Cultured; Cyclic AMP; Cyclic GMP; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocytes; Prostaglandins E

Topics: Adult; Aged; Cells, Cultured; Cyclic AMP; Cyclic GMP; Folic Acid; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphocytes; Middle Aged; Prostaglandins E; Sialic Acids; Vitamin B 12

Topics: Cell Cycle; Colony-Forming Units Assay; Cyclic AMP; Cyclic GMP; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Leukemia, Myeloid; Macrophages; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic