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

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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of high dose methotrexate (HDMTX) therapy on plasma hypoxanthine (Hx) and uridine (UR) concentrations in 12 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). The initial plasma Hx level before the first administration of HDMTX (1 g/m2) was significantly higher in patients (25.5 +/- 17.5 microM) than that in healthy adult controls (4.0 +/- 1.4 microM). By 48 or 72 hours after the beginning of MTX infusion, the Hx concentration had decreased to 7.9 +/- 7.7 microM and 4.7 +/- 4.1 microM, respectively. This decrease of plasma Hx concentration after MTX infusion was also observed with the second course of HDMTX (3 g/m2) therapy. On the other hand, the plasma UR level did not change significantly. The in vitro treatment with 2 microM MTX of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient mutant cells selected from HL-60 lowered the excretion of Hx into the culture medium. These data suggest a possible new explanation of the synergism of HDMTX and 6-thiopurines, for example 6-mercaptopurine and 6-thioguanine, since plasma Hx is considered to counteract 6-thiopurine toxicity through competition at the level of HGPRT.
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PMID:Effect of high-dose methotrexate on plasma hypoxanthine and uridine levels in patients with acute leukemia or non-Hodgkin lymphoma in childhood. 143 5

The clonal composition of each cell population was determined from the characteristic methylation pattern of DNA and the restriction fragment length polymorphism (RFLP) of the hypoxanthine phosphoribosyltransferase (HPRT) and phosphoglycerate kinase (PGK) genes, both located on the X chromosome. About 71% of Japanese females are heterozygous in terms of the RFLP of either HPRT or PGK genes, which was demonstrated by using 5' genomic DNA or cDNA probes for these genes. All 3 cases of chronic myeloproliferative disorders showed monoclonal patterns. AML or ALL cases demonstrated either monoclonal or polyclonal patterns depending upon the percentage of blastic cells. Monoclonal patterns were seen in 3 of 4 cases of myelodysplastic syndromes and both PNH cases.
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PMID:Molecular genetic approach to the analysis of clonal proliferation in hematologic disorders. 257 94

Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) patients consistently show a rearrangement in a 5.8-kilobase length of chromosome 22, referred to as the breakpoint cluster region (bcr). In Ph1-positive acute lymphoblastic leukemia (ALL), the breakpoint in chromosome 22 is more heterogeneous and, in some instances, does not occur within this region. In such cases the cell of origin of the neoplastic clone and the relationship of the disease to CML has remained obscure. We have analyzed the bcr rearrangement in the malignant cells from three patients who presented with Ph1-positive ALL and who in cytogenetic studies had shown evidence of variable involvement of myeloid cells in the Ph1-positive clone. Rearrangements in bcr typical of most cases of CML were detected in purified granulocyte preparations from two of the ALL patients (nos. 1 and 2) and in the blasts from patient 3 at the time of her terminal relapse. In the same analysis the simultaneously obtained granulocytes from patient 3, however, did not show any evidence of bcr rearrangement. Patient 3 was also heterozygous for the BamHI polymorphism in the X-linked hypoxanthine phosphoribosyltransferase (HPRT) gene, thus permitting a different method of clonal analysis based on methylation differences in active and inactive alleles. When DNA from her granulocytes that had shown no bcr rearrangement was hybridized to an HPRT probe, a pattern typical of a polyclonal population was seen. A similar pattern was exhibited by her marrow fibroblasts. In marked contrast, her simultaneously isolated blasts showed an unambiguous monoclonal pattern. These findings demonstrate the origin of the disease in the first two patients in a cell with myelopoietic as well as lymphopoietic potential and confirm the restricted lymphoid cell origin of the neoplastic clone in the third Ph1-positive ALL patient. Furthermore, they indicate that different target cells for transformation within the hematopoietic system may be affected by very similar bcr rearrangements.
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PMID:Molecular analysis of clonality and bcr rearrangements in Philadelphia chromosome-positive acute lymphoblastic leukemia. 289 31

Adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), 5'nucleotidase (5'NT), ecto-5'NT, hypoxanthine-guanine phosphoribosyltransferase(HGPRT), adenine phosphoribosyltransferase(APRT), adenosine kinase(AK), AMP deaminase (AMPD) and adenylate kinase(AdKin) activities were assayed in leukemic cells from bone marrow and/or peripheral blood of 43 newly diagnosed children with acute lymphoblastic leukemia(ALL). These enzyme activities have been investigated in relation to some immunological markers. ADA activity was higher in E-rosette positive leukemia(E+ ALL), while HGPRT, APRT, PNP, 5'NT, ecto-5'NT and AdKin activities were found to be lower in E+ ALL as compared to E- ALL. In common ALL (cALL) antigen positive leukemia, mean ADA activity was significantly lower as compared to cALL- leukemia, whereas PNP, 5'NT, ecto-5'NT and AdKin activities were significantly higher. cALL cells with cytoplasmic immunoglobulin M(IgM) heavy chains were found to have mean 5'NT activities twice as high as cALL cells lacking cytoplasmic IgM heavy chains. In two patients who had surface immunoglobulins on their cell membranes, low 5'NT activities were found. When measuring enzyme activities after 2-4 days of prednisone monotherapy, only mean ADA and HGPRT activities decreased in non-B, non-T ALL. These decreases were not significant in T-ALL patients. Mean enzyme activities in the leukemic cells of five patients with relapse were comparable to those in newly diagnosed patients, except for 5'NT, which was found to be within the activity range of control peripheral blood lymphocytes. It is concluded that ADA and AdKin activities are suitable as markers for E+ ALL and cALL+ leukemias respectively. 5'NT might help to distinguish between cALL cells having and lacking pre-B characteristics. Since 5'NT activity may also be decreased in B-ALL, it is not suitable as a T-ALL marker. Enzymes of purine metabolism in leukemic relapse need further investigation.
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PMID:Purine metabolism in childhood acute lymphoblastic leukemia: biochemical markers for diagnosis and chemotherapy. 631 Feb 74

Validity of measurement of somatic cell mutation frequency (Mf) at the hprt locus for evaluating cancer risk of the given individual was determined in pediatric patients. Peripheral lymphocytes (PL) from patients with various diseases, including acute lymphoblastic leukemia (ALL) and Hodgkin's disease (HD), DNA repair deficient syndromes or short stature receiving growth hormone (GH), were isolated through Ficoll-Hypaque sedimentation with informed consent. Mf at the hprt locus of PL was determined by limiting dilution assay using 6-thioguanine (6-TG). Results were as follows. (1) ALL patients after chemotherapy had higher Mf than that of age-matched controls. (2) Patients with HD tended to have higher Mf after chemotherapy. (3) Among DNA-repair deficient syndromes, diseases which are susceptible to cancer (Xeroderma pigmentosum, Ataxia telangiectasia) have high Mf, but those without any cancer disposition (Cockayne syndrome, Rothmund-Thomson syndrome) have normal Mf. (4) GH-receiving patients have normal Mf, regardless of total doses of GH. Measurement of Mf at HPRT locus may be useful for evaluating cancer risk of pediatric patients.
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PMID:Measurement of mutation frequency at the HPRT locus in peripheral lymphocytes. Is this a good method to evaluate a cancer risk in pediatric patients? 959 52

T cells from patients who had received chemotherapy for B-lineage acute lymphocytic leukemia were studied to determine whether genetic instability, a principal characteristic of cancer cells, can also occur in nonmalignant cells. Consistent with expectations for a genetic instability phenotype, multiple mutations were detected in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene in independently isolated mutant T cells expressing identical rearranged T cell receptor beta (TCRbeta) gene hypervariable regions. These results indicate that cancer treatment can lead to genetic instability in nonmalignant cells in some individuals. They also suggest a mechanistic paradigm for the induction of second malignancies and drug resistance.
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PMID:Emergence of genetic instability in children treated for leukemia. 1077 10

There is continued controversy as to the sequential steps and mechanism(s) responsible for the in vivo acquisition of multiple mutations during neoplastic transformation. We investigated the in vivo clonality and mutational spectra of hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations in T cells from children with acute lymphocytic leukemia (ALL) to gain insight into the mutagenic mechanisms associated with leukemogenesis. We observed several instances of multiple, independent HPRT mutations accumulating in vivo in T cell receptor (TCR) gene defined clones that had undergone extensive pre- and/or post-thymic expansion following chemotherapy. In addition, we also detected the accumulation of multiple unique single mutations within distinct expanding post-thymic T cell clones. This pattern of clonally restricted hypermutability is compatible with extensive cell proliferation and selection alone without postulating genomic instability. These observations provide a paradigm for a continuum of cellular events that eventually results in the clonal accumulation of mutations in selected populations of cells in vivo and may provide insight into the primary genetic events associated with leukemogenesis, as well as the development of second malignancies and drug resistance following chemotherapy.
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PMID:Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia. 1175 11

6-Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogs of the natural purines: hypoxanthine and guanine. Both mercaptopurine and thioguanine are substrates for hypoxanthine-guanine phosphoribosyltransferase and are converted into the ribonucleotides 6-thioguanosine monophosphate (6-thioGMP) and 6-thioinosine monophosphate (T-IMP) respectively. The accumulation of these monophosphates inhibits several vital metabolic reactions. Today, these thiopurine bases remain valuable agents for the induction and maintenance of remissions in patients with myelocytic and acute lymphocytic leukemia. Despite their proved clinical importance, 6MP and 6TG have certain therapeutic disadvantages, which have continued to stimulate the search for purine derivatives enhancing therapeutic efficacy. Considerable efforts have been made to prepare other novel mercaptopurine and thioguanine analogs and their nucleosides to improve the antitumor efficacy. The effectiveness of these thiopurines against certain tumor cell lines suggested that some of these mercaptopurine analogs and their nucleosides would be worthy of consideration in order to determine whether they exert a more selective effect against neoplastic cells than against normal cells or they might be useful in patients whose disease has become resistant to 6MP or 6TG. This review will focus on mercaptopurine analogs and their nucleosides as antimetabolite agents.
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PMID:Thioguanine, mercaptopurine: their analogs and nucleosides as antimetabolites. 1452 46

Because de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 +/- 57 versus 1001 +/- 31 or versus 1315 +/- 76 fmol/nmol/h, P <.0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1-positive and TEL-AML1-negative ALL (P <.001, false discovery rate [FDR] = 5%). The pattern of expression of these 16 genes discriminated TEL-AML1-positive ALL with a true accuracy of 84% in an independent test set (n = 17, confidence interval 70% to 94%, P <.001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism.
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PMID:Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis. 1514 81

The survival rates of children treated for cancer have dramatically increased after the development of standardized multiple-modality treatment protocols. As a result, there is a rapidly growing population of pediatric cancer survivors in which the long-term genotoxic effects of chemotherapeutic intervention is unknown. To study the genotoxic effects of antineoplastic treatment in children, we performed a comparative analysis of the changes in the frequency of somatic mutations (Mfs) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT)-reporter gene in children treated for acute lymphocytic leukemia (ALL). We measured HPRT Mfs from 130 peripheral blood samples from 45 children with ALL (13, low risk; 22, standard risk; and 10, high risk) from the time of diagnosis, as well as during and after the completion of therapy. We observed a significant increase in mean HPRT Mfs during each phase of therapy (diagnosis, 1.4 x 10(-6); consolidation, 52.1 x 10(-6); maintenance, 93.2 x 10(-6); and off-therapy, 271.7 x 10(-6)) that were independent of the risk group treatment protocol used. This 200-fold increase in mean somatic Mf remained elevated years after the completion of therapy. We did not observe a significant difference in the genotoxicity of each risk group treatment modality despite differences in the compositional and clinical toxicity associated with these treatment protocols. These findings suggest that combination chemotherapy used to treat children with ALL is quite genotoxic, resulting in an increased somatic mutational load that may result in an elevated risk for the development of multi-factorial diseases, in particular second malignancies.
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PMID:Genotoxicity of therapeutic intervention in children with acute lymphocytic leukemia. 1523 55


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