Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.3.5 (
5'-nucleotidase
)
3,167
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The pyrimidine analogue cytosine arabinoside (
AraC
) is one of the most effective drugs used in the treatment of acute leukaemia. Overexpression of the multidrug resistance (MDR-1) gene and its product, P-glycoprotein (P-gp), is associated with cellular resistance to drugs, such as anthracyclines and vinca alkaloids. This resistance can be reversed by cyclosporine analogues or verapamil (ver). We investigated the in vitro cross-resistance to
AraC
in a doxorubicin-resistant HL60 cell line, with an elevated expression of the MDR-1 gene. The resistant clone showed an eightfold increased resistance to
AraC
and a two- to fourfold resistance to the other analogues, as measured by cytotoxicity test. There was no significant increase in the activity of
5'-nucleotidase
or in the amount of deoxyribonucleotide pools between cell lines. We could, however, detect a reduction in deoxycytidine kinase (dCK) activity (30%, P = 0.021, using deoxycytidine as substrate) and the level of
AraC
triphosphates was significantly reduced in the resistant cells (70%, P = 0.009). When the cells were exposed to cyclosporin A (CsA) or the cyclosporine analogue PSC 833 (PSC) in combination with
AraC
, there was more extensive apoptosis, as measured by formation of oligonucleosomal DNA fragmentation and caspase-3-like activity, than with exposure to
AraC
alone. We also found an increased retention of
AraC
in the resistant cells when incubated with
AraC
in combination with CsA. Ver in combination with
AraC
, failed to increase apoptosis for the resistant cell line. Our data suggests that the resistance to
AraC
for the P-gp-expressing cells is a result of a reduction of dCK activity and an increase in efflux, the latter possibly depending on P-gp. A combination of CsA or PSC with
AraC
may improve the effect of
AraC
in vivo.
...
PMID:Cross-resistance to cytosine arabinoside in a multidrug-resistant human promyelocytic cell line selected for resistance to doxorubicin: implications for combination chemotherapy. 1155 80
De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue
AraC
, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and -451C>T rs532545),
5'-nucleotidase
(cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3'UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and -451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML.
...
PMID:Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase. 2387 72
