Abstract:
:High-dose cytosine arabinoside (AraC)-containing regimens have shown the highest antileukaemic efficacy of all currently used regimens in the treatment of acute myeloid leukaemia (AML). This study aimed at increasing the antileukaemic potential of high-dose AraC by raising intracellular levels of AraC triphosphate (AraCTP), which is the mediator of cytotoxicity, via biochemical modulation by inhibitors of ribonucleotide reductase (RR) or haematopoietic growth factors (HGFs). Blasts from patients with de novo AML were analysed for their formation of AraCTP under high-dose AraC conditions (20 microM over 3 h) without prior modulation (n = 47) after a 2-h pre-exposure with fludarabine (50 microg/ml) (n = 40) or gemcitabine (30 ng/ml) (n = 40) and after a 48-h pre-exposure to granulocyte colony-stimulating-factor (G-CSF; 100 ng/ml) (n = 27) or granulocyte-macrophage colony-stimulating-factor (GM-CSF; 100 U/ml) (n = 28). Unmodulated formation of AraCTP (median 239.8 ng/107 cells) could not be increased via modulation by gemcitabine (232.4 ng/107 cells) or fludarabine (247.8 ng/107 cells). The lack of effect of RR inhibitors was also observed for all other known metabolites of AraC [Ara-cytosine monophosphate (CMP), Ara-cytosine diphosphate (CDP), AraCDP-choline, Ara-uridine monophosphate (UMP), Ara-uridine diphosphate (UDP) and Ara-uridine triphosphate (UTP)]. In contrast, pre-exposure to HGFs led to significant increases in AraCTP formation (G-CSF 556.0 ng/107 cells, 2.31-fold increase, P < 0.001; GM-CSF 447.9 ng/107 cells, 1.87-fold increase, P < 0.0001). To establish the mechanism responsible for these effects, the activity of the rate-limiting enzyme of AraC metabolism, deoxycytidine kinase (dCK), was investigated (n = 33). In vivo exposure to GM-CSF led to increases in dCK activity from unmodulated values at 0 h (29.8 pmol/min/mg protein) to 34.3 pmol/min/mg protein at 24 h (1.15-fold increase) and 54.5 pmol/min/mg protein at 48 h (1. 83-fold increase). The raise in dCK activity over 48 h was significant (P < 0.013).
journal_name
Br J Haematoljournal_title
British journal of haematologyauthors
Braess J,Wegendt C,Jahns-Streubel G,Kern W,Keye S,Unterhalt M,Schleyer E,Hiddemann Wdoi
10.1046/j.1365-2141.2000.02056.xsubject
Has Abstractpub_date
2000-05-01 00:00:00pages
388-95issue
2eissn
0007-1048issn
1365-2141pii
bjh2056journal_volume
109pub_type
杂志文章abstract::Autologous or allogeneic peripheral blood T cells can stimulate the human megakaryocyte progenitor cell (CFU-Meg)-derived colony formation in a dose-dependent fashion in agar cultures of nonadherent (NA), T cell-depleted (NT) bone marrow (BM) cells. Low concentrations of monocytes and T cells can collaborate in the st...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1990.tb07830.x
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abstract::The in vitro haemostatic functions of fresh whole blood (FWB) are well preserved after cold storage. This study aimed to determine whether platelets derived from FWB and stored whole blood (SWB) contribute to clot formation in tissue injury after transfusion into coagulopathic rats with polytrauma/haemorrhage (T/H). T...
journal_title:British journal of haematology
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journal_title:British journal of haematology
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abstract::A novel human leukaemia cell line, designated TMD7, was established from blast cells of a patient with de novo acute myeloblastic leukaemia with trilineage myelodysplasia (AML/TLD). As seen in the original blast cells, TMD7 cells expressed CD7, CD13, CD33 and CD34 and showed an abnormal karyotype containing -5, -7, -8...
journal_title:British journal of haematology
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1988.tb02507.x
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journal_title:British journal of haematology
pub_type: 杂志文章
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journal_title:British journal of haematology
pub_type: 杂志文章
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journal_title:British journal of haematology
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journal_title:British journal of haematology
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journal_title:British journal of haematology
pub_type: 杂志文章
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journal_title:British journal of haematology
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doi:10.1046/j.1365-2141.1996.d01-1691.x
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journal_title:British journal of haematology
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pub_type: 杂志文章
doi:10.1111/j.1365-2141.1975.tb00870.x
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journal_title:British journal of haematology
pub_type: 杂志文章
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journal_title:British journal of haematology
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journal_title:British journal of haematology
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doi:10.1046/j.1365-2141.1998.00729.x
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journal_title:British journal of haematology
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doi:10.1046/j.1365-2141.1999.01135.x
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journal_title:British journal of haematology
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journal_title:British journal of haematology
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doi:10.1111/j.1365-2141.1975.tb01798.x
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journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1982.tb01961.x
更新日期:1982-04-01 00:00:00
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journal_title:British journal of haematology
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doi:10.1111/j.1365-2141.1979.tb01129.x
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journal_title:British journal of haematology
pub_type: 杂志文章
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journal_title:British journal of haematology
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journal_title:British journal of haematology
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journal_title:British journal of haematology
pub_type: 杂志文章
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abstract::Follow-up studies of natural killer (NK) cells, NK activity and antibody dependent cellular cytotoxicity (ADCC) in the course of hairy cell leukaemia (HCL) were carried out in a series of patients affected by the disease. NK activity against K562 targets was found to be high in all the patients with non-symptomatic st...
journal_title:British journal of haematology
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journal_title:British journal of haematology
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