Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.4 (deaminase)
 5,113 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Though data from cell lines are abundant, the reason for the development of resistance to 1-beta-D arabinofuranosylcytosine (ara-C) in vivo remains unresolved. A broad interpatient variation of metabolic parameters has further complicated interpretation of the results. The present study compares ara-C metabolism in leukemic blasts of two patients with newly diagnosed disease, before and after repeated treatment with ara-C containing chemotherapy regimens in vivo. Membrane transport of ara-C was unchanged after treatment. In addition, cell-free extracts of blasts obtained after treatment failure showed an unchanged cytidine deaminase activity. Though deoxycytidine kinase activity in cell extracts was unaltered or increased after treatment failure, the activity in situ, measured as the rate of 1-beta-D-arabinofuranosylcytosine triphosphate (ara-CTP) formation, was decreased. This could be shown to be due to an expansion of the deoxycytidine triphosphate (dCTP) pool. The severalfold increase in dCTP pool was accompanied by a decrease in thymidine triphosphate (dTTP) pool and correlated with a decrease in deoxycytidylate deaminase (dCMP-deaminase) activity in cell free extracts. Low dCMP-deaminase activity had been shown to confer an ara-C resistant phenotype to cell lines in vitro. Data presented in this paper show that a selection for leukemic blasts with low dCMP-deaminase activity can also be favored by ara-C containing treatment regimens in vivo. Our data suggest that this mechanism might contribute to treatment failure.
Leukemia 1990 Nov
PMID:Concordant changes of pyrimidine metabolism in blasts of two cases of acute myeloid leukemia after repeated treatment with ara-C in vivo. 223 89

To establish the most effective and reasonable mode of combining and administrering ara-C with other antileukemic agents in chemotherapy for acute leukemia, the action mechanisms of ara-C was investigated in terms of intracellular pharmacodynamics and the biochemical action mechanism of ara-C was investigated in leukemic cell. Rensonable methods of administering the agent was considered as follows. 1. A low level of ara-C in the incubation medium induced a higher concentration of ara-CTP in leukemic cells. Therefore, maintenance of even a low plasma ara-C level after ara-C therapy could enhance the antileukemic effect of the agent. 2. Ara-C activation was increased in the presence of 6MP by suppressing elevation of deaminase activity in the cell suspection medium. Therefore, administration of 6MP prior to ara-C therapy could enhance the antileukemic effect of the agent. 3. Ten micrograms/ml of ara-C, corresponding to intermediate dose ara-C therapy, induced rapid endonuclease activation, DNA ladder fragmentation and subsequent apoptosis in large numbers of leukemic cells, suggesting that intermediate dose ara-C therapy is effective in reducing residual leukemic cells after therapy. 4. Blood transfusion for patients with high grade anemia prior to bebenoyl ara-C therapy prolonged higher and longer plasma drug maintenance. 5. Flowcytometry of cell cycle progression of L1210 cells treated by ara-C and daunorubicin revealed that a combination of ara-C first and daunorubicin second was superior to the reverse sequential combination. These improvements in the mode of administering ara-C could provide better results following chemotherapy for leukemia.
Leukemia 1997 Apr
PMID:Intracellular pharmacodynamics of ara-C and flowcytometric analysis of cell cycle progression in leukemia chemotherapy. 920 53

The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR-ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDDeltaE4a, with a 30-bp deletion of exon 4; AIDDeltaE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDDeltaE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-DeltaE4a and AID-DeltaE3E4 variants, whereas the C-terminal-truncated AID-DeltaE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability.
Leukemia 2010 Jan
PMID:Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients. 1975 60

The MIR-15A/-16-1 tumor suppressor microRNAs (miRNAs) are deleted in leukemic cells from more than 50% of patients with chronic lymphocytic leukemia (CLL). As these miRNAs are also less abundant in patients without genomic deletion, their downregulation in CLL is likely to be caused by additional mechanisms. We found the primary transcripts (pri-miRNAs) of MIR-15a/-16/-15b to be elevated and processing intermediates (precursor miRNAs) to be reduced in cells from CLL patients (22/38) compared with non-malignant B-cells (n=14), indicating a block of miRNA maturation at the DROSHA processing step. Using a luciferase reporter assay for pri-miR processing we validated the defect in primary CLL cells. The block of miRNA maturation is restricted to specific miRNAs and can be found in the cell line MEC-2, but not in MEC-1, even though both are derived from the same CLL patient. In these cells, the RNA-specific deaminase ADARB1 leads to reduced pri-miRNA processing, but full processing efficiency is recovered upon deletion of the RNA-binding domains or nuclear localization of ADARB1. Thus, we show that, apart from genomic deletion or transcriptional downregulation, aberrant processing of miRNA leads to specific reduction of miRNAs in leukemic cells. This represents a novel oncogenic mechanism in the pathogenesis of CLL.
Leukemia 2014 Jan
PMID:Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia. 2397 81