Lack of cross-resistance between cytosine arabinoside and a new halogenated nucleoside analogue, 2-bromo-2?-deoxyadenosine in human acute myeloid leukaemia cells

1987 ◽  
Vol 20 (2) ◽  
Author(s):  
LuciaB. Pemble ◽  
MichelleG. Lihou ◽  
RaymondL. Blakley ◽  
GaryP. Jamieson ◽  
PeterJ. Smith
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Nucleoside Analogue ◽  
Cytosine Arabinoside ◽  
Cross Resistance ◽  
Acute Myeloid

scholarly journals Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Tamara Rothenburger ◽  
Dominique Thomas ◽  
Yannick Schreiber ◽  
Paul R. Wratil ◽  
Tamara Pflantz ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cell Lines ◽  
Nucleoside Analogue ◽  
Acquired Resistance ◽  
Nucleoside Analogues ◽  
Cross Resistance ◽  
Enzymatic Assays ◽  
Anti Cancer ◽  
Acute Myeloid

Abstract Background SAMHD1 mediates resistance to anti-cancer nucleoside analogues, including cytarabine, decitabine, and nelarabine that are commonly used for the treatment of leukaemia, through cleavage of their triphosphorylated forms. Hence, SAMHD1 inhibitors are promising candidates for the sensitisation of leukaemia cells to nucleoside analogue-based therapy. Here, we investigated the effects of the cytosine analogue CNDAC, which has been proposed to be a SAMHD1 inhibitor, in the context of SAMHD1. Methods CNDAC was tested in 13 acute myeloid leukaemia (AML) cell lines, in 26 acute lymphoblastic leukaemia (ALL) cell lines, ten AML sublines adapted to various antileukaemic drugs, 24 single cell-derived clonal AML sublines, and primary leukaemic blasts from 24 AML patients. Moreover, 24 CNDAC-resistant sublines of the AML cell lines HL-60 and PL-21 were established. The SAMHD1 gene was disrupted using CRISPR/Cas9 and SAMHD1 depleted using RNAi, and the viral Vpx protein. Forced DCK expression was achieved by lentiviral transduction. SAMHD1 promoter methylation was determined by PCR after treatment of genomic DNA with the methylation-sensitive HpaII endonuclease. Nucleoside (analogue) triphosphate levels were determined by LC-MS/MS. CNDAC interaction with SAMHD1 was analysed by an enzymatic assay and by crystallisation. Results Although the cytosine analogue CNDAC was anticipated to inhibit SAMHD1, SAMHD1 mediated intrinsic CNDAC resistance in leukaemia cells. Accordingly, SAMHD1 depletion increased CNDAC triphosphate (CNDAC-TP) levels and CNDAC toxicity. Enzymatic assays and crystallisation studies confirmed CNDAC-TP to be a SAMHD1 substrate. In 24 CNDAC-adapted acute myeloid leukaemia (AML) sublines, resistance was driven by DCK (catalyses initial nucleoside phosphorylation) loss. CNDAC-adapted sublines displayed cross-resistance only to other DCK substrates (e.g. cytarabine, decitabine). Cell lines adapted to drugs not affected by DCK or SAMHD1 remained CNDAC sensitive. In cytarabine-adapted AML cells, increased SAMHD1 and reduced DCK levels contributed to cytarabine and CNDAC resistance. Conclusion Intrinsic and acquired resistance to CNDAC and related nucleoside analogues are driven by different mechanisms. The lack of cross-resistance between SAMHD1/ DCK substrates and non-substrates provides scope for next-line therapies after treatment failure.

Mitozantrone and cytosine arabinoside as first-line therapy in elderly patients with acute myeloid leukaemia

1991 ◽  
Vol 79 (3) ◽  
pp. 415-420 ◽  
Author(s):  
J. A. Liu Yin ◽  
P. R. E. Johnson ◽  
J. M. Davies ◽  
N. G. Flanagan ◽  
D. W. Gorst ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cytosine Arabinoside ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Acute Myeloid

A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia

Leukemia ◽  
2015 ◽  
Vol 29 (6) ◽  
pp. 1312-1319 ◽  
Author(s):  
A K Burnett ◽  
N Russell ◽  
R K Hills ◽  
N Panoskaltsis ◽  
A Khwaja ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Nucleoside Analogue ◽  
Older Patients ◽  
Low Dose ◽  
The Novel ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

IN VITRO RESISTANCE TO CYTOSINE ARABINOSIDE, NOT TO DAUNORUBICIN, IS ASSOCIATED WITH THE RISK OF RELAPSE IN DE NOVO ACUTE MYELOID LEUKAEMIA

1996 ◽  
Vol 93 (4) ◽  
pp. 903-910 ◽  
Author(s):  
Edwin Klumper ◽  
Gert J. Ossenkoppele ◽  
Rob Pieters ◽  
Dieuwke R. Huismans ◽  
Annemarie H. Loonen ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cytosine Arabinoside ◽  
De Novo ◽  
Risk Of Relapse ◽  
Acute Myeloid
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