The influence of 1-β- D-arabinofuranosylcytosine on the metabolism of phosphatidylcholine in human leukemic HL 60 and Raji cells

Berkovic, Dinko; Fleer, E. A. M.; Breass, J.; Pförtner, J.; Schleyer, E.; Hiddemann, Wolfgang

doi:10.1038/sj.leu.2400860

Cited by 16 publications

(11 citation statements)

References 18 publications

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“…Cytosine arabinoside (Ara-C) exhibits cytotoxic effects on leukemia cells by inhibiting the activity of DNA polymerase and becoming incorporated into newly synthesized DNA at the S-phase. Berkovic et al (1997) reported that high-dose Ara-C treatment leads to a reduction of cell membrane PC content in HL-60 cells. The addition of lysophosphatidylcholine (lysoPC), which is a direct precursor for PC, increases the PC content of the cell membrane and antagonized the cytotoxic effect.…”

Section: Discussionmentioning

confidence: 99%

Effects of recombinant human PLD2 on proliferation and apoptosis of HL‐60 cells

Zhu

Ya-xiong

Yu³

2008

Cell Biology International

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In the present study, we investigated the role of recombinant human phospholipase D2 (rhPLD2) on proliferation and apoptosis in human leukemia HL-60 cells which induced by camptothecin. Our research demonstrated that various concentrations of rhPLD2 inhibit the growth of HL-60 cells in a dose-dependent manner, and rhPLD2 plus camptothecin can produce a synergistic effect on growth inhibition of HL-60 cells in vitro. So, we conclude that rhPLD2 alone cannot induce apoptosis in HL-60 cells, but it can potentiate the apoptosis of HL-60 cells induced by camptothecin. Similarly, we show that both rhPLD2 and standard PLD were able to enhance camptothecin-induced apoptosis of HL-60 cells.

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Section: Discussionmentioning

confidence: 99%

Effects of recombinant human PLD2 on proliferation and apoptosis of HL‐60 cells

Zhu

Ya-xiong

Yu³

2008

Cell Biology International

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“…Also, during dose escalation of AraC the ratio of AraCDP-choline to AraCTP rose from 17% to 20% in blasts and from 11% to 16% in NBMMC (not statistically significant, P ¼ 0·25 and 0·16). Since AraCDP-choline is implicated in the rapid blast lysis during high-dose AraC regimens, the preferential formation of this metabolite in leukaemic blasts might contribute to this phenomenon (Berkovic et al, 1997;Daly et al, 1990;Kucera & Capizzi, 1992;Lauzon et al, 1978). Our data are in accordance with data from other groups who have also demonstrated a higher formation of AraCTP in leukaemic cells than in NBMMC.…”

Section: Discussionmentioning

confidence: 99%

“…The drug exerts its cyctotoxicity via several interconnected mechanisms of action which still remain to be fully elucidated: AraC monophosphate (AraCMP) is incorporated into the DNA and acts as a relative chain terminator (Kufe et al, 1980(Kufe et al, , 1984, enzymes of DNA metabolism (polymerases a and b) are inhibited (Harrington & Perrino, 1995;Leclerc et al, 1987;Mutsukage et al, 1978;Ohno et al, 1988) as are mechanisms of DNA repair (Gedik & Collins, 1991). Alterations of phospholipid metabolism (Berkovic et al, 1997;Daly et al, 1990;Kucera & Capizzi, 1992) and direct interactions with cellular membranes (Koehler et al, 1985) may contribute to cellular lysis particularly during high-dose AraC treatment. In recent years perturbations of cellular signal transduction pathways during AraC exposure have been described potentially leading to apoptosis (Ibrado et al, 1996;Kuwakado et al, 1995).…”

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confidence: 99%

Leukaemic blasts differ from normal bone marrow mononuclear cells and CD34+ haemopoietic stem cells in their metabolism of cytosine arabinoside

Braess

Wegendt²,

Feuring-Buske

et al. 1999

Br J Haematol

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Different metabolites of cytosine arabinoside (AraC) contribute to its cytotoxicity including incorporation of AraCTP into DNA, the incorporation of AraUMP into RNA, inhibition of polymerase alpha and beta (AraCMP/CTP), an impairment of repair mechanisms (AraCTP), alterations of phospholipid metabolism (AraCDP-choline), a direct membrane interaction (AraC), the alteration of signal transduction pathways (AraCDP-choline, AraCTP) and the induction of apoptosis. Since little is known about the potential differences in AraC metabolism between leukaemic blasts and normal haemopoietic progenitor cells, the formation of all known AraC metabolites was determined in bone marrow samples from patients with acute myeloid leukaemia (AML), healthy volunteers and specimens of cellsorted CD34+ haemopoietic stem cells. Highly significant differences were found for phosphorylated AraC metabolites (AraCMP, -CDP, -CTP, AraUMP) between AML and normal mononuclear bone marrow (ng/107 cells respectively 1.30 v 2.66; 2.65 v 7.50; 33.68 v 99.0; 1.18 v 5.70). The highest differences were found for formation of AraCDP-choline (3.75 v 12.86) which might be relevant for the high efficacy of high-dose AraC regimens. In contrast, no differences were found in the deamination product AraU (2.01 v 2.91). Only minute amounts of phosphorylated AraU derivatives were detected, providing an explanation for the lacking contribution of AraU to cytosine arabinoside cytotoxicity. Results in normal CD34+ haemopoietic stem cells did not differ significantly from normal bone marrow mononuclear cells and therefore justify their use as a surrogate in determining AraC-induced haematotoxicity. These data suggest a metabolic basis for the relative selectivity of AraC cytotoxicity for AML blasts and provide a means to determine the role of different metabolites and their related mechanism of action for overall AraC cytotoxicity.

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“…Moreover, the correlation of a high EPA and a response to AraC treatment as shown in this study as well as in a previous investigation (Jahns Streubel et al, 1995) was based on standard dose AraC and hence cannot be extrapolated to, for example, high-dose AraC protocols. This has to be considered in view of the observation that the rapid blast clearance after high-dose AraC might be caused by interactions of AraCTP and/or AraCDP choline with the phospholipid metabolism of cellular membranes (Koehler et al, 1985;Daly et al, 1990;Berkovic et al, 1997). High-dose AraC-induced cytotoxicity would therefore not necessarily require rapidly dividing cells, which is a potential explanation for efficacy of such regimens in relapsed or primarily refractory AML in which standard dose AraC combinations have proved to be unsuccessful.…”

Section: Discussionmentioning

confidence: 99%

The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside‐based treatment regimens in acute myeloid leukaemia with a high proliferative activity

et al. 2000

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Summary. The current study was initiated to explore the mechanisms underlying the previously demonstrated association between the proliferative activity of leukaemic blasts and the response to cytosine arabinoside (AraC)-based therapy in de novo acute myeloid leukaemia (AML). The activity of key enzymes of AraC metabolism±deoxycytidine kinase (DCK), cytidine deaminase (DCD) and polymerase a (PolyA) were determined in blast cells from 33 patients. In addition, formation and retention of intracellular levels of AraC triphosphate (AraCTP) and DNA incorporation of AraC were measured, as was the proliferative activity of leukaemic blasts by [ 3 H]-TdR incorporation before and after stimulation with granulocyte±macrophage colonystimulating factor (GM-CSF) or granulocyte CSF (G-CSF) for 48 h. AraC incorporation into the DNA (median 0´60 pmol/10 5 cells) was significantly related to the proliferative activity of AML blasts (r 0´74, P , 0´001). Similarly, priming with GM-CSF or G-CSF increased both the proliferative activity of AML blasts by a median of 1´84-and 1´64-fold, respectively, and the incorporation of AraC into the DNA (1´29-and 1´40-fold respectively). In contrast, no relationship was found between the endogenous proliferative activity (EPA) and enzyme activities regulating AraC activation (DCK; median 4´70 pmol/min/mg protein), inactivation (DCD; median 2´92 pmol/min/mg protein) or inhibitory effects (PolyA; median 1´50 pmol/min/mg protein), nor the formation or retention of AraCTP (median 306´1 ng/10 7 cell and 1´6 h respectively). When samples were grouped according to EPA (more than or less than the median), slowly proliferating specimens had a higher response to cytokine priming for proliferative activity and incorporation of AraC into DNA. Clinical data of 15 patients were available. Although all eight patients with a high endogenous proliferative activity reached complete remission, only four out of seven patients with a low proliferative activity responded, whereas the other three patients were non-responders (P 0´077).

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The influence of 1-β- D-arabinofuranosylcytosine on the metabolism of phosphatidylcholine in human leukemic HL 60 and Raji cells

Cited by 16 publications

References 18 publications

Effects of recombinant human PLD2 on proliferation and apoptosis of HL‐60 cells

Effects of recombinant human PLD2 on proliferation and apoptosis of HL‐60 cells

Leukaemic blasts differ from normal bone marrow mononuclear cells and CD34+ haemopoietic stem cells in their metabolism of cytosine arabinoside

The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside‐based treatment regimens in acute myeloid leukaemia with a high proliferative activity

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