5-methyltetrahydrofolate and Leukemia--Myeloid--Acute

High doses of (dl)-5-methyltetrahydrofolate (mTHF) cause strong inhibition of growth of leukemic cell lines. We studied the effect of mTHF, at concentrations ranging from 10(-3) M to 10(-4) M, on peripheral leukemic cells obtained from 15 acute non-lymphocytic leukemia (ANLL) patients, by [3H]-thydimidine uptake inhibition. Unlike leukemic cell lines, mTHF exerts a variable effect on ANLL cells in primary culture. While about 33% of cases are strongly inhibited, 55% are only slightly affected, showing a reduction in growth comparable to normal cell populations tested (unstimulated and PHA-stimulated lymphocytes, day 7 and day 14 colony forming units-granulocyte/monocyte (CFU-GM), normal blast colonies). In a minority of cases we observed stimulation of growth. This study reflects the metabolic variability of single-case leukemic cell populations, possibly in relationship to folate transport and accumulation.

Topics: Adolescent; Adult; Cell Division; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Phytohemagglutinins; Tetrahydrofolates; Tumor Cells, Cultured

The 90-min-uptake (37 degrees C) of 3H-methotrexate (3H-MTX) by uninduced HL60 cells was inhibited by 2,4-dinitrophenol, iodoacetate, ouabain, p-chloromercuriphenylsulphate and p-chloromercuribenzoate indicating its dependence on intracellular ATP, the Na+ and K+-activated ATPase of the cell membrane and sulphydryl groups on the cell surface. There was a marked reduction in the 90-min-uptake (37 degrees C) of 3H-MTX and 14C-methyltetrahydrofolate (14C-mTHF) when HL60 cells were induced to differentiate into neutrophil myelocytes and metamyelocytes by incubation with DMSO; a smaller reduction was seen when HL60 cells were induced to differentiate into mononuclear phagocytes by incubation with 1 alpha,25-dihydroxyvitamin D3 ([OH]2D3). Although it has been reported that the transport system mediating folate uptake has a higher Km value for mTHF and MTX in normal than in malignant cells, the Km values for these substrates were lower in blood-monocyte-derived macrophages than in uninduced HL60 cells or [OH]2D3-induced-macrophages. Values for the 90-min-uptake (37 degrees C) of 3H-MTX and 14C-mTHF in human blood-monocyte-derived macrophages were higher than the corresponding values in uninduced HL60 cells and [OH]2D3-induced macrophages.

Topics: Biological Transport, Active; Calcitriol; Cell Differentiation; Depression, Chemical; Dimethyl Sulfoxide; Humans; Leukemia, Myeloid, Acute; Macrophages; Male; Methotrexate; Sodium-Potassium-Exchanging ATPase; Tetrahydrofolates; Tumor Cells, Cultured