Imbalance in the ribonucleotide pools of lymphoid cells from acute lymphoblastic leukemia patients

Korte, Dirk de; Haverkort, Willem A.; Roos, Dirk; Behrendt, H.; Gennip, Albert H.

doi:10.1016/0145-2126(86)90068-8

Cited by 22 publications

(4 citation statements)

References 22 publications

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“…Alterations in ribonucleotide pools have been observed in various malignancies (Jackson et al, 1980;Weber et al, 1983;De Korte et al, 1987;Slingerland et al, 1995) including lymphoblasts of paediatric patients with ALL, with the increase in CTP concentration being most pronounced (De Korte et al, 1986). Our study showed that there seems to be a correlation between the activity of CTP synthetase and the concentration of CTP in the patients' samples.…”

Section: Discussionsupporting

confidence: 54%

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

Verschuur

Gennip²,

Leen³

et al. 2000

Br J Haematol

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Summary. Cytidine triphosphate (CTP) synthetase is a key enzyme for the synthesis of cytosine (deoxy)ribonucleotides, catalysing the conversion of uridine triphosphate (UTP) into CTP, and has a high activity in several malignancies. In this preclinical study, the enzyme activity and mRNA expression of the enzyme and (deoxy)ribonucleotide concentrations were analysed in leukaemic cells of 57 children suffering from acute lymphocytic leukaemia (ALL). In addition, in vitro experiments were performed with the CTP synthetase inhibitor cyclopentenyl cytosine (CPEC). A significantly higher activity of CTP synthetase (6´5^3´9 nmol CTP/ mg/h) was detected in ALL cells than in lymphocytes of healthy controls (1´8^0´9 nmol CTP/mg/h, P , 0´001) that was independent of white blood cell (WBC) count, blast percentage, age, gender or type of ALL. The enzyme activity was not correlated with the CTP synthetase mRNA expression. The activity of CTP synthetase in ALL cells compared with non-malignant CD341 bone marrow controls (5´6^2´4 nmol CTP/mg/h) was not statistically different. In vitro treatment of ALL cells with CPEC induced a dose-dependent decrease of the CTP concentration. The lowest concentration of CPEC (0´63 mm) induced a depletion of CTP of 41^20% and a depletion of dCTP of 27^21%. The degree of CTP depletion of ALL cells after treatment with CPEC was positively correlated with the activity of CTP synthetase. The inhibition of CTP synthetase in situ was confirmed by flux studies using radiolabelled uridine. From these results, it can be expected that CPEC has a cytostatic effect on lymphoblasts of children with ALL.

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Section: Discussionsupporting

confidence: 54%

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

Verschuur

Gennip²,

Leen³

et al. 2000

Br J Haematol

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“…2). High concentrations of CTP 15 and dCTP 16 have been observed in human leukemic cells that can be correlated to a high activity of CTP synthetase, which is responsible for the conversion of UTP into CTP (Fig. 2).…”

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confidence: 97%

Cyclopentenyl cytosine increases the phosphorylation and incorporation into DNA of 1‐β‐D‐arabinofuranosyl cytosine in a human T‐lymphoblastic cell line

Verschuur

Gennip

Leen

et al. 2002

Intl Journal of Cancer

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The cytotoxic effect of 1-␤-D-arabinofuranosyl cytosine (araC) depends on the intracellular phosphorylation into its active compound araCTP, on the degree of degradation of araCTP and on the incorporation of araCTP into DNA. Deoxycytidine triphosphate (dCTP) inhibits the phosphorylation of araC (by feedback inhibition of the enzyme deoxycytidine kinase) and the incorporation of araCTP into DNA (by competition for DNA polymerase). In a T-lymphoblastic cell line, we studied whether the cytotoxicity of araC (2 nM-50 M) could be enhanced by decreasing the concentration of dCTP, using the nucleoside-analogue cyclopentenyl cytosine (CPEC), an inhibitor of the enzyme CTP synthetase. Preincubation of the cells with CPEC (100 -1,600 nM) for 2 hr increased the concentrations of araCMP 1.6 -9.5-fold, which was significant for each concentration of CPEC used. The concentration of araCDP remained low, whereas the concentration of araCTP changed depending on the concentration of araC used. With 2-15 M of araC and a preincubation with 400 nM of CPEC, the araCTP concentration increased by 4 -15% (not significant), and the total amount of araC nucleotides increased significantly by 21-45%. When using a concentration of araC of 2 nM after a preincubation with CPEC of 100 nM, the concentration of araCMP increased by 60% (p ‫؍‬ 0.015), whereas that of araCTP decreased by 10% (p ‫؍‬ 0.008). This was compensated by an increase of 41% (p ‫؍‬ 0.005) of araCTP incorporation into DNA, which represented 43% of all araC metabolites. Moreover, by performing pulse/chase experiments with 400 nM of CPEC and 2 M of araC, the retention of cytosolic araCTP and the incorporated amount of araCTP into DNA were increased by CPEC. The modulation by CPEC of araC metabolism was accompanied by a synergistic increase of araC-induced apoptosis and by an additive effect on the araC-induced growth inhibition. © 2002 Wiley-Liss, Inc. Key words: cytarabine; deoxycytidine kinase; dCTP; CTP synthetase; cyclopentenyl cytosine 1-␤-D arabinofuranosyl cytosine (araC) is a nucleoside analogue that constitutes the main drug of virtually all treatment protocols for AML and proved its benefit in precursor-B acute lymphocytic leukemia (ALL) and T-ALL. 1-3 One can distinguish low-dose (LD-araC) regimens, applying doses of 75-200 mg/m 2 , from high-dose (HD-araC) regimens where 1-3 g/m 2 are used. The cytotoxic effect of araC depends on several intracellular mechanisms: araC is metabolized into arabinofuranosyl cytosine triphosphate (araCTP) by 3 consecutive phosphorylating steps, catalyzed by deoxycytidine kinase (dCK), nucleoside monophosphate (NMP) kinase and nucleoside diphosphate (NDP) kinase, respectively (Fig. 1). AraCTP is incorporated into DNA as a deoxynucleotide-analogue, where it exerts its cytotoxic properties by inhibiting DNA replication. 4 -6 The phosphorylation of araC into araCTP can be counteracted by the enzyme (deoxy)cytidine deaminase, which converts araC into arabinofuranosyl uracil (araU), dCMP deaminase, converting arabinofuranosyl cytosine mon...

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“…Proliferation is a common feature of all lymphoid cells with deviations in the nucleotide pool, although the proliferation rate of CLL lymphocytes is very low (Dameshek, 1977). We have been unable to find a correlation between the proliferation rate and the degree of deviations in the nucleotide pool for ALL lymphoblasts (De Korte et al, 19866) and promyelocytic HL-60 cells (De Korte et al, 1986~). We suggest that, superimposed on deviations caused by commitment for proliferation, malignant transformation also leads to a decrease in the various nucleotide ratios.…”

Section: Discussionmentioning

confidence: 83%

Aberrant ribonucleotide pattern in lymphoid cells from patients with chronic lymphocytic leukaemia or non‐Hodgkin lymphoma

Korte

Roos

et al. 1987

Intl Journal of Cancer

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The intracellular purine and pyrimidine ribonucleotide concentrations were determined in lymphoid cells from peripheral blood of 16 patients with chronic lymphocytic leukaemia (CLL) and from peripheral blood and/or lymphoid tissue of 18 patients with non-Hodgkin lymphoma (NHL). Compared to normal peripheral lymphocytes, the lymphoid cells from CLL patients contained lower, and those from NHL patients higher amounts of nucleotides. The lymphoid cells of NHL patients showed an imbalance in the nucleotide pool compared to either normal resting peripheral or proliferating tonsillar lymphocytes. The lymphoid cells of patients with CLL showed an imbalance only when compared to normal, resting peripheral lymphocytes. The abnormalities in the nucleotide pools involved decreased ratios of purine:pyrimidine, adenine:guanine and uracil:cytosine nucleotides. Lymphocytes from CLL and NHL patients contained increased amounts (relative and/or absolute) of UDP sugars, and NHL lymphocytes also showed a changed composition of the UDP sugars. Analysis of the ribonucleotides in the lymphoid cells provides useful information for the differential diagnosis of patients suspected of having CLL or NHL, and may be valuable for the design of new chemotherapeutic regimens.

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Imbalance in the ribonucleotide pools of lymphoid cells from acute lymphoblastic leukemia patients

Cited by 22 publications

References 22 publications

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia

Cyclopentenyl cytosine increases the phosphorylation and incorporation into DNA of 1‐β‐D‐arabinofuranosyl cytosine in a human T‐lymphoblastic cell line

Aberrant ribonucleotide pattern in lymphoid cells from patients with chronic lymphocytic leukaemia or non‐Hodgkin lymphoma

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