Purine metabolism in myeloid precursor cells during maturation. Studies with the HL-60 cell line.

Lucas, Diane L.; Webster, H. K.; Wright, Daniel G.

doi:10.1172/jci111152

Cited by 96 publications

(25 citation statements)

References 33 publications

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“…Mycophenolic acid (MPA) noncompetitively inhibits IMP dehydrogenase, the rate-controlling enzyme for de novo biosynthesis of GMP, thus depleting cellular pools of GTP and dGTP (14,26). Because lymphoid cells cannot use the salvage pathway for purine synthesis (3), depletion of dGTP inhibits DNA replication (6,21).…”

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confidence: 99%

Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes

Alfieri

Allison

Kieff

1994

Antimicrob Agents Chemother

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minute, with a Betaplate scintillation counter (Pharmacia LKB Biotechnology Inc., Piscataway, N.J.). By 3 days postinfection, large cell clumps were evident only in cultures exposed to MPA concentrations of less than 1.0 ,uM, a concentration which inhibited thymidine uptake in both EBV-infected and uninfected cells ( Fig. 1; see below).Indirect immunofluorescence microscopy was performed 4 days after primary B-lymphocyte infection, with monoclonal antibodies PE2 and CS1-4 (27) (donated by L. Young and A. Rickinson, Birmingham, England), which are reactive to EBV nuclear antigen 2 (EBNA-2) and latent membrane protein 1 (LMP-1), respectively. A goat anti-mouse secondary antibody conjugated to fluorescein isothiocyanate (Jackson ImmunoResearch Laboratories Inc., West Grove, Pa.) was added in a secondary step. The results in Table 1 indicate that 2 to 5% and 1 to 2% of the cells expressed EBNA-2 and LMP-1, respectively, following a single round of cell division. This expression of EBNA-2 and LMP-1 was not affected by an MPA concentration of 0.1 or 0.01 ,uM. However, 1.0 ,uM MPA inhibited, but did not completely block, EBNA-2 and LMP-1 expression, thereby reducing the number of EBNA-2-and LMP-1-expressing cells to 1% or less. At concentrations higher than 1.0 ,uM MPA, no further reduction in EBNA-2 and LMP-1 expression was noted, indicating that even high concentrations of MPA could not completely block EBNA-2 and LMP-1 expression. A 50% reduction of EBNA-2 and LMP-1 fluorescence might be expected because of a nonspecific antiproliferative effect of MPA (see below), since the first round of cell division after EBV infection of B lymphocytes in vitro is between 36 and 72 h postinfection (1,19,25). Since both EBNA-2 and LMP-1 are putative mediators of EBV-induced B-cell transformation (12), the inability of MPA to inhibit their expression completely might indicate that MPA cannot prevent initiation of the transforming process.MPA concentrations of 1.0 ,uM and above inhibited the outgrowth of EBV-transformed cells (Fig. 1). However, even this was likely due to an antiproliferative effect of MPA rather than an effect on EBV initiation or maintenance of transformation, since reversibility studies showed that treatment with 2.5 ,uM MPA from the time of infection to 5 days

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confidence: 99%

Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes

Alfieri

Allison

Kieff

1994

Antimicrob Agents Chemother

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“…Inhibitors of IMP dehydrogenase were found to be cytotoxic towards several tumour lines including those unresponsive to other chemotherapeutic agents (Sweeney et al, 1972;Carney et al, 1985;Connoly & Halsall, 1975). IMP dehydrogenase inhibitors have recently been shown to induce cell differentiation in the promyelocytic cell line HL-60 (Lucas et al, 1983;Wright, 1987).…”

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Growth inhibition and induction of phenotypic alterations in MCF-7 breast cancer cells by an IMP dehydrogenase inhibitor

Sidi

Panet²,

Wasserman³

et al. 1988

Br J Cancer

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“…In both normal and malignant cells, the activity of this enzyme is positively correlated with cellular growth rate (26,27). Furthermore, in tumor cells IMPDH inhibitors cause a dose-dependent reduction in growth (10,13,22) and in the human promyelocytic HL-60 leukemia cell line also cause a dose-dependent induction of cell maturation (12,20). These observations suggest that IMPDH activity and the production of guanine nucleotides are involved in the regulation of growth and differentiation in mammalian cells.…”

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Amplification of the IMP dehydrogenase gene in Chinese hamster cells resistant to mycophenolic acid.

Collart¹,

Huberman²

1987

Mol. Cell. Biol.

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The regulation of IMP dehydrogenase (IMPDH) was analyzed in Chinese hamster V79 cell variants that exhibit different degrees of resistance to the cytotoxic effect of mycophenolic acid, a specific inhibitor of IMPDH. Western blot (immunoblot) analysis with an IMPDH antiserum revealed a 14-to 27-fold increase in the amount of enzyme in the mycophenolic acid-resistant cells. The antiserum was also used to screen for a phage containing the IMPDH cDNA sequence from a Agtll expression library. Northern blot (RNA blot) analyses of total cellular and poly(A)+ RNA showed that an IMPDH cDNA probe hybridized to a 2.2-kilobase transcript, the amount of which was associated with increased resistance. Southern blotting with the probe indicated an amplification of the IMPDH gene in the mycophenolic acid-resistant cells. Our findings suggest that the acquired mycophenolic acid resistance of the V79 cell variants is associated with increases in the amount and activity of IMPDH and the number of IMPDH gene copies.IMP dehydrogenase (IMPDH) (EC 1.2.1.14), an enzyme that regulates guanine nucleotide biosynthesis, catalyzes the reaction of the branch point in the synthesis of adenine and guanine nucleotides. In both normal and malignant cells, the activity of this enzyme is positively correlated with cellular growth rate (26,27). Furthermore, in tumor cells IMPDH inhibitors cause a dose-dependent reduction in growth (10,13,22) and in the human promyelocytic HL-60 leukemia cell line also cause a dose-dependent induction of cell maturation (12,20). These observations suggest that IMPDH activity and the production of guanine nucleotides are involved in the regulation of growth and differentiation in mammalian cells.To study the control of IMPDH in mammalian cells, we isolated from the Chinese hamster V79 cell line, variants with altered IMPDH activity. The variants were obtained by treating the V79 cells with 0.5 ,ug of N-methyl-N-nitro-Nnitrosoguanidine and then selecting colonies of cells in the presence of 1 ,ug of mycophenolic acid (MPA), a cytotoxic IMPDH inhibitor (4), per ml as described previously (6). The resistance level of one of these cell variants was further increased by a stepwise selection in the presence of increasing concentrations of MPA. After adaptation to the higher concentration of MPA, the cells were seeded in medium containing an increased concentration of MPA at 200 cells per 60-mm petri dish, and MPA-resistant colonies were isolated 8 days later. This procedure, which was repeated a number of times, resulted in four cell clones, VM1 through VM4, which were resistant to 5, 10, 25, and 50 jig of MPA per ml, respectively, whereas the parental V79 cells were resistant to only 0.1 ,ug of MPA per ml (Table 1). The increased resistance to MPA cytotoxicity in the variant cells was associated with an increased IMPDH activity in their cell homogenates, with VM1 cells exhibiting about a 6-fold increase in IMPDH activity over the parental cells and VM2, VM3, and VM4 cells expressing about 7-, 9-, and 11-fold increases, re...

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Purine metabolism in myeloid precursor cells during maturation. Studies with the HL-60 cell line.

Cited by 96 publications

References 33 publications

Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes

Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes

Growth inhibition and induction of phenotypic alterations in MCF-7 breast cancer cells by an IMP dehydrogenase inhibitor

Amplification of the IMP dehydrogenase gene in Chinese hamster cells resistant to mycophenolic acid.

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