Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To isolate murine purine nucleoside phosphorylase-encoding cDNA sequences (PNP), a murine BALB/c liver cDNA library in lambda gt10 was screened for recombinants hybridizing to a human PNP cDNA probe. Two of three clones recovered included inserts large enough to contain the full-length coding sequence. Sequence analysis of the largest clone revealed an 867-nucleotide open reading frame encoding 289 amino acids with 84% residue identity to that encoded by human PNP and 351 bp of 3'-untranslated region. The 5' end of the murine PNP message was specifically amplified by PCR using the RACE (rapid amplification of cDNA ends) protocol, revealing a 5'-untranslated region of 78 bp. Northern hybridization using the murine PNP cDNA sequence as a probe identified a message of approx. 1.6 kb in mouse NIH3T3 cells which was slightly smaller than the human message observed in HeLa cells. The cloned murine PNP cDNA coding sequence was inserted into a mammalian expression vector under transcriptional regulation of the Moloney murine leukemia virus long terminal repeat. Transfection of this plasmid into human 293 cells resulted in the expression of PNP activity which co-focused with murine PNP activity extracted from NIH3T3 cells, verifying that the isolated murine PNP cDNA clone encoded catalytically active PNP protein.
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PMID:Isolation and expression of a murine purine nucleoside phosphorylase-encoding cDNA and sequence similarity with the human message. 137 46

To determine the effectiveness of retroviral-mediated purine nucleoside phosphorylase (PNP) gene transfer and expression for metabolic correction of PNP deficiency, we used as a gene transfer target the NSU-1 subline of murine S49 T lymphoma cells, an in vitro genetic model of PNP deficiency. NSU-1 cells were transduced with recombinant retroviruses that express either the murine or human PNP coding sequences under transcriptional regulation of the Moloney murine leukemia virus (Mo-MLV) long terminal repeat (LTR), resulting in expression of substantial levels of PNP activity. Untransduced or control virus-transduced NSU-1 cells were extremely sensitive to deoxyguanosine, a PNP substrate that is toxic for lymphoid cells. However, PNP-virus transduction of NSU-1 cells metabolically corrected the sensitivity of these cells to deoxyguanosine, resulting in near wild-type levels of growth inhibition. These results demonstrate that retroviral-mediated PNP gene transfer and expression corrects the metabolic defect observed in PNP-deficient murine lymphoid cells, suggesting that PNP gene transfer and expression in human lymphoid cells might similarly correct substrate-mediated toxicity and provide an effective genetic therapy.
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PMID:Correction of purine nucleoside phosphorylase deficiency by retroviral-mediated gene transfer in mouse S49 T cell lymphoma: a model for gene therapy of T cell immunodeficiency. 148 2

Many reports have described the relationship of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) activities with the immunological subclasses of acute lymphoblastic leukemia (ALL). The clinical significance of these enzymes in leukemias is not yet completely understood. We performed a study in 83 children with untreated ALL to establish the relationships of ADA and PNP to clinical outcome, in vitro drug resistance and differentiation stage of B-cell lineage ALL. ADA and PNP activities were determined radiochemically. In vitro resistance to 6-thioguanine (6-TG) was determined with the MTT assay. ADA activity was not different between proB- and cALL cases but decreased in the sequential differentiation stages cALL----preB-ALL----B-ALL. The PNP level was not different between the four stages of B-lineage ALL. Patients with cALL/preB ALL with low ADA activities had a significantly poorer probability of survival (p = 0.005) than patients with high ADA levels. Patients with cALL/preB ALL with low PNP activities showed a non-significant trend for a poorer prognosis (0.05 less than p less than 0.10) than patients with a high PNP level. Low ADA and PNP activities were not related to in vitro resistance to 6-TG. We conclude that ADA decreases and PNP remains constant in sequential differentiation stages of B-lineage ALL. Patients with precursor B-lineage ALL with low activities of ADA have a poorer prognosis than those with high activities of these enzymes. No relationship could be detected between ADA or PNP activity and resistance to 6-TG.
Leukemia 1992 May
PMID:Adenosine deaminase and purine nucleoside phosphorylase in childhood lymphoblastic leukemia: relation with differentiation stage, in vitro drug resistance and clinical prognosis. 159 2

Proviral DNA derived from a recombinant retroviral vector (LHMlPL), constructed to transduce the human purine nucleoside phosphorylase coding region along with the mouse metallothionein l promoter, was molecularly cloned in order to characterize a deletion previously observed in this provirus. Nucleotide sequence comparison with the original retroviral vector construct revealed two deletions in the cloned provirus. One of the deleted regions originated entirely from within the mouse metallothionein promoter. A second deletion eliminated portions of both viral and metallothionein promoter sequences. All four deletion junctions in the original construct included sequences which conform to those proposed as eukaryotic consensus splice donor and acceptor signals, including a previously unreported cryptic splice donor signal in the Moloney leukemia virus envelope gene. It is concluded that RNA splicing between inadvertently juxtaposed donor and acceptor signals was responsible for the observed deletions.
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PMID:Deletion in a recombinant retroviral vector resulting from a cryptic splice donor signal in the Moloney leukemia virus envelope gene. 211 58

This report summarises the current knowledge regarding the clinical utility of biochemical enzyme markers for both diagnostic and therapeutic purposes in acute leukaemia. The enzymes studied most extensively in this field are terminal deoxynucleotidyl transferase, adenosine deaminase, 5'-nucleotidase, purine nucleoside phosphorylase, and acid phosphatase, esterase, hexosaminidase isoenzymes. For each enzyme, the quantitative and qualitative characteristics in various immunologically defined subclasses of acute leukaemia are described. The quantitative evaluation of enzyme activities represents an adjunctive classification technique which should be incorporated into the multivariate analysis, the "multiple marker analysis." By qualitative characterisation pronounced heterogeneity of leukaemia subsets is uncovered. The application of 2'-deoxycoformycin, a specific inhibitor of adenosine deaminase, and the potential usefulness of two other enzymes as targets for treatment with selective agents is discussed. The concept that gene products expressed at certain developmental stages of normal cells can similarly be detected in leukaemic cells (which therefore seem to be "frozen" or "arrested" at this particular maturation/differentiation stage) is supported by the results obtained in enzyme studies. Besides their practical clinical importance for classification and treatment of acute leukaemias, biochemical enzyme markers constitute a valuable research tool to disclose biological properties of leukaemic cells.
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PMID:Biochemical enzyme analysis in acute leukaemia. 298 4

The multidisciplinary approach of leukemia phenotyping, called multiple marker analysis, led to changes in the classification systems of normal hematopoiesis and leukemic cells, and introduced the use of a biological and functional definition of leukemia, rather than merely morphological-cytochemical descriptions. Two major conclusions can be drawn from the findings of multiple marker analysis: 1) differentiation of leukemia is not abnormal but blocked ("maturation arrest"), and leukemic cells retain normal maturation-linked markers; and 2) no leukemia specific marker could be detected so far. Although leukemic cells show general qualitative features in common with normal cells, some quantitative characteristics of these similar attributes are peculiar to leukemic blasts. Qualitative and quantitative enzymological characteristics help to identify the cell lineage involved and to determine the developmental point at which maturation arrest occurs. The expression of isoenzymes is often linked to the presumptive sequence of developmental stages. Subsets within ALL subtypes showed pronounced modifications in their isoenzyme patterns associated with increasing maturity. Thus, enzyme markers can provide refined definitions of subgroups by biochemical criteria. Based on recent observations using the enzyme markers TdT, adenosine deaminase, 5'-nucleotidase, purine nucleoside phosphorylase, acid phosphatase, and hexosaminidase, a scheme of enzymological expression in the various commonly accepted subtypes of acute lymphoid leukemia and acute nonlymphoid leukemia is presented. Enzyme marker analysis represents a useful tool as an adjunctive method in multiple marker analysis for assessing diagnosis, prognosis, and the evolutionary and pathogenetic mechanisms underlying the spectrum of leukemia subtypes. Furthermore, enzyme marker analysis may provide further insight into certain aspects of the pathobiology of leukemia which might not be elucidated by other methods.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Significance of enzyme markers as a part of multiple marker analysis in leukemia research. 300 Feb 10

Investigations of the purine degradative enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and ecto-5'-nucleotidase (5'NT) have been shown to be of value in defining subsets of lymphoid malignancies. We have studied the activities of these enzymes in the circulating malignant cells of 35 patients with chronic B lymphocytic leukaemia and have correlated the biochemical data with immunological phenotypes. Classification of the cases into those without evidence of secretory activity ('true' CLL, 14 patients) and those with cytoplasmic immunoglobulin (CIg) ('immunocytoma'; 21 patients) revealed that immunocytomas are phenotypically and biochemically associated with more mature features. Malignant cells without CIg were characterized by low activities of ADA, PNP and 5'NT. In malignant cells with evidence of secretory activity (immunocytoma), low activity of ADA was also observed, but the activities of PNP and 5'NT were relatively high and approached the range of normal B lymphocytes. The differences in PNP (P less than 0.05) and in 5'NT (P less than 0.01) between these two groups were significant. Phenotypically the cells without CIg were predominantly associated with IgM (+k light chains) as surface membrane immunoglobulin (SmIg) whereas expression of IgG was more often observed in the leukaemic cells with CIg. No correlation between enzyme patterns and the stage of the disease was apparent. Thus both biochemical and immunological criteria show that cases of CLL vary within a range of maturity and that those with CIg might be more mature in the B cell axis. The present study emphasizes the value of purine enzyme studies in defining subsets of B cell neoplasia.
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PMID:Purine degradative enzymes and immunological phenotypes in chronic B-lymphocytic leukaemia: indications that leukaemic immunocytoma is a separate entity. 300 40

Purine nucleoside phosphorylase (PNP) activity was determined in mononuclear cells from 49 patients with various types of leukemia. A low level of PNP activity was found in mononuclear cells from patients with acute myeloid and lymphoblastic leukemia and with chronic lymphocytic leukemia. Enzymatic and immunological studies on PNP from leukemic cells of these patients revealed no differences in Michaelis constant for inosine, thermostability, electrophoretic mobility, immunological reactivity, or specific activity between the PNP of leukemic cells and that of normal mononuclear cells. These results suggest that the decrease in PNP activity of leukemic cells is due to a decreased rate of enzyme synthesis. Thus, the abnormality of PNP activity might be due to an alteration in the regulatory mechanism of enzyme synthesis in the purine metabolism in the leukemic clone.
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PMID:Characterization of purine nucleoside phosphorylase in leukemia. 309 66

Total adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) activities were measured in cell samples from 13 cases of de novo acute leukemia and from three cases of chronic myeloid leukemia in blast crisis (CMLBC). These cases could be separated into lymphoid and nonlymphoid types on the basis of enzyme activity, with two misclassifications. However, PNP activity added little or no discriminatory information. Analysis for expression of the various molecular weight (mol wt) ADA isozymes, ADA1 (40 Kd) and ADA2 (110 Kd), revealed that ADA2 was expressed exclusively in nonlymphoid cells whereas ADA1 was found in both lymphoid and nonlymphoid cell types. Identification of ADA2 divided these leukemia cases into lymphoid and nonlymphoid types with no misclassifications (P = .0002; Fisher's exact test). Acute nonlymphoblastic leukemia (ANLL) with a monocytic component tended to have a greater percentage of ADA2 than ANLL without a monocytic component. These studies suggest that ADA2 may be a novel biochemical marker for an immature nonlymphoid cell.
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PMID:Differential expression of adenosine deaminase isozymes in acute leukemia. 314 Sep 11

After four days of treatment with 10(-8) M TPA, differentiation of the human T-lymphoblastoid cell line MOLT-4 was induced along the T cell lineage, confirmed by a fall in adenosine deaminase and 5'-ectonucleotidase and a rise in purine nucleoside phosphorylase activity. TPA-treated cells became resistant to the cytotoxic effects of 1-beta-D-arabinofuranosylcytosine (Ara-C), 9-beta-D-arabinofuranosyladenine (Ara-A), and 2-chlorodeoxyadenosine. This was, in part, due to the altered cell cycle distribution (accumulation of cells in the G1 phase), since the toxicity of Ara-C and Ara-A is S phase specific. The diminished rate of Ara-C transport concomitant with Ara-CTP formation after TPA treatment is considered to be the biochemical basis for this acquired resistance.
Leukemia 1988 Jul
PMID:Changes in sensitivity to anticancer drugs during TPA-induced cellular differentiation in a human T-lymphoblastoid cell line (MOLT-4). 326 Jun 48


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