Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), a selective inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, provided in end stage leukemic patients a rapid decrease of IMP dehydrogenase activity and GTP concentration in the blast cells and a subsequent decline in blast cell count. Sixteen consecutive patients with end stage acute nonlymphocytic leukemia or myeloid blast crisis of chronic granulocytic leukemia were treated with tiazofurin. Allopurinol was also given to inhibit xanthine oxidase activity to decrease uric acid excretion and to elevate the serum concentration of hypoxanthine, which should competitively inhibit the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the salvage enzyme of guanylate synthesis. Assays of IMP dehydrogenase activity and GTP concentration in leukemic cells provided a method to monitor the impact of tiazofurin and allopurinol and to adjust the drug doses. In this group of patients with poor prognosis, five attained a complete hematological remission and one showed a hematological improvement. A marked antileukemic effect was seen in two other patients. All five evaluable patients with myeloid blast crisis of chronic granulocytic leukemia reentered the chronic phase of their disease. Five patients with acute nonlymphocytic leukemia were refractory to tiazofurin and three were unevaluable for hematological effect because of early severe complications. Responses with intermittent 5- to 15-day courses of tiazofurin lasted 3-10 months. Tiazofurin had a clear antiproliferative effect, but the pattern of hematological response indicated that it appeared to induce differentiation of leukemic cells. In spite of toxicity with severe or life-threatening complications in 11 of 16 patients, tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational, biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy.
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PMID:Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity. 256 8

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

Determination of cellular clonality in hematological malignancies provides fundamental information that is important in understanding the pathogenesis of these disorders. We present here an extension of one approach to accomplish this that is based on the interpretation of different methylation patterns on active and inactive X chromosomes within the region of the hypoxanthine-guanine phosphoribosyltransferase gene spanned by a restriction fragment length polymorphism. The successful application of the method to determine clonality is described for three female patients with acute nonlymphocytic leukemia.
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PMID:Determination of clonality in acute nonlymphocytic leukemia by restriction fragment length polymorphism and methylation analysis. 288 56

Aplastic anaemia (AA) can be associated with disorders that are known to exhibit clonal haematopoiesis, like paroxysmal nocturnal haemoglobinuria (PNH), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). It appears that the long term survivors of severe AA treated with immunosuppressive agents such as ATG have a continuing, late mortality caused by the evolution of clonal disorders which are not usually seen when bone marrow transplant is used. In children, typical AA may precede the onset of acute lymphoblastic leukemia (ALL). The aplastic phase is often transient and remission may be spontaneous or rapidly induced by steroid, and followed a few months later by acute leukaemia. This modality of presentation may be observed in up to 2-3% of all cases of paediatric ALL. A 13-year old girl who presented with two spontaneously reversible episodes of marrow aplasia has been reported recently. She developed ALL 8 months later. Southern analysis showed identical clonal immunoglobulin heavy chain gene rearrangement bands in her leukaemic cells as well as the marrow cells obtained at the two aplastic episodes. Hypoxanthine phosphoribosyltransferase polymorphism studies showed that all the ALL blast cells, bone marrow and peripheral cells during the two aplastic episodes all exhibited clonal haematopoiesis with the same X-chromosome inactivated. This case provides strong evidence that AA and ALL can represent evolution of the same abnormal clone.
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PMID:Childhood acute lymphoblastic leukaemia and aplastic anaemia. 806 86

Etoposide is one of the most widely used antineoplastics. Unfortunately, the same treatment schedules associated with impressive efficacy are associated with an increased risk of secondary acute myeloid leukemia (AML), which has prompted its withdrawal from some treatment regimens, thereby potentially compromising efficacy against the original tumor. Because etoposide-associated AML is characterized by site-specific illegitimate DNA recombination, we studied whether etoposide could directly cause site-specific deletions of exons 2 and 3 in the hprt gene. Human lymphoid CCRF-CEM cells were treated with etoposide for 4 hours, and DNA was isolated after subculturing. The deletion of exons 2 and 3 from hprt was assayed by a quantitative polymerase chain reaction (PCR) method. In the absence of etoposide treatment, the frequency of deletions of exons 2 and 3 was very low (5.05 x 10(-8)). After exposure to 10 mumol/ L etoposide, the frequency of the exon 2 + 3 deletion was increased immediately after and at 24 hours after etoposide treatment (65 to 89 x 10(-8)) and increased to higher levels (128 to 173 x 10(-8)) after 2 and 6 days of subculture (P < .001 overall). The frequency of the exon 2 + 3 deletion assessed at 6 days of subculture after 4 hours of 0, 0.25, 1, 2.5, 5, and 10 mumol/L etoposide treatment increased with etoposide concentration, ie, 5.05 x 10(-8), 89.2 x 10(-8), 108 x 10(-8), 142 x 10(-8), 163 x 10(-8), and 173 x 10(-8), respectively (P < .0001). Sequencing of a subset of amplified products confirmed the presence of DNA sequences at the breakpoints consistent with V(D)J recombination. By contrast, exon 2 + 3 deletions after etoposide treatment in the myeloid cell lines KG-1A and K562 showed no evidence of V(D)J recombinase in their genesis. We conclude that etoposide can induce the illegitimate site-specific action of V(D)J recombinase on an unnatural DNA substrate after a single treatment in human lymphoid cells.
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PMID:Etoposide causes illegitimate V(D)J recombination in human lymphoid leukemic cells. 882 41

Etoposide is among the most widely used anti-cancer drugs. Its use, however, has been associated with increased risk of secondary acute myeloid leukemia (AML) which is characterized by chromosomal translocations suggesting involvement of recombination-associated motifs at the breakpoints. A PCR-based assay was developed to quantitate the frequency of two illegitimate V(D)J recombinase-mediated genomic rearrangements-a 20-kb deletion in the hprt gene and the bcl2/IgH translocation (t(14;18)) found in non-Hodgkin's lymphoma. We examined both lymphocyte and non-lymphocyte blood cell DNA of children with acute lymphoblastic leukemia (ALL) for changes in the frequencies of these biomarkers during etoposide therapy to determine the level of illegitimate V(D)J recombination changes during therapy. A low level of t(14;18) was found in the lymphocytes before etoposide treatment, which was significantly reduced during etoposide therapy. In before-etoposide samples, no t(14;18) were found among 7.72x107 non-lymphocytes; during treatment none were found among 1.87x108 non-lymphocytes. Deletions were not found before etoposide treatment in either the lymphocytes (6.67x107) or non-lymphocytes (5.43x107) and were non-significantly elevated during etoposide therapy (1 in 1.4x108 lymphocytes and 1 in 1.39x108 non-lymphocytes). It is interesting to note the one patient with an hprt deletion mutation in non-lymphocytes; V(D)J recombination is not normally found in this cell type, but is the cell type from which AML derives. Several patients had clones of t(14;18)-bearing cells as determined by DNA sequence analysis. These results suggest that this etoposide-based chemotherapy was ineffective in producing genomic rearrangements mediated by illegitimate V(D)J recombination in these patients.
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PMID:The frequency of illegitimate V(D)J recombinase-mediated mutations in children treated with etoposide-containing antileukemic therapy. 980 12

Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme for the synthesis of GTP and dGTP. Two isoforms of IMPDH have been identified. IMPDH Type I is ubiquitous and predominantly present in normal cells, whereas IMPDH Type II is predominant in malignant cells. IMPDH plays an important role in the expression of cellular genes, such as p53, c-myc and Ki-ras. IMPDH activity is transformation and progression linked in cancer cells. IMPDH inhibitors, tiazofurin, selenazofurin, and benzamide riboside share similar mechanism of action and are metabolized to their respective NAD analogues to exert antitumor activity. Tiazofurin exhibits clinical responses in patients with acute myeloid leukemia and chronic myeloid leukemia in blast crisis. These responses relate to the level of the NAD analogue formed in the leukemic cells. Resistance to tiazofurin and related IMPDH inhibitors relate mainly to a decrease in NMN adenylyltransferase activity. IMPDH inhbitors induce apoptosis. IMPDH inhitors are valuable probes for examining biochemical functions of GTP as they selectively reduce guanylate concentration. Incomplete depletion of cellular GTP level seems to down-regulate G-protein function, thereby inhibit cell growth or induce apoptosis. Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes the dehydrogenation of IMP to XMP utilizing NAD as the proton acceptor. Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthesis of guanylates, including GTP and dGTP. The importance of IMPDH is central because dGTP is required for the DNA synthesis and GTP plays a major role not only for the cellular activity but also for cellular regulation. Two isoforms of IMPDH have been demonstrated. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II enzyme is predominant in malignant cells. Although guanylates could be salvaged from guanine by the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the level of circulating guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates in the cells.
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PMID:Consequences of IMP dehydrogenase inhibition, and its relationship to cancer and apoptosis. 1039 Jun 1