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)

Thiopurinol [4-thiopyrazolo(3.4-dyprimidine, TPP] and its ribonucleoside (TPPR) were effective in vitro against the intracellular and extracellular forms of L. braziliensis and L. mexicana. They also inhibited the transformation of the amastigote of L. donovani to the promastigote. These thio-analogues had about the same activity as allopurinol [4-hydroxypyrazolo(3.4-d)pyrimidine, HPP] and its ribonucleoside (HPPR). the thiopyrazolopyrimidines were converted primarily to the ribonucleoside-5' -phosphate (TPPR-MP) and to an unidentified metabolite, but not to any of the adenine ribonucleoside analogues previously shown to be formed from allopurinol and its ribonucleoside. There was an antagonism between the growth-inhibitory effects of allopurinol and thiopurinol. This is consistent with the findings that the intracellular concentrations of TPP and TPPR-MP are sufficient to inhibit the conversion of allopurinol to allopurinol ribonucleotide (HPPR-MP) by the hypoxanthine-guanine phosphoribosyltransferase by 30 per cent and the amination of HPPR-MP by adenylosuccinate synthetase by 50 per cent respectively. Consequently, the incorporation of the aminated product (aminopyrazolopyrimidine) into RNA was substantially decreased. The difference in metabolism between the thio- and hydroxypyrazolopyrimidines suggests a difference in their mechanisms of action against the pathogenic leishmania.
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PMID:Antileishmanial action of 4-thiopyrazolo (3.4-d) pyrimidine and its ribonucleoside. Biological effects and metabolism. 707 76

The growth inhibitory mechanisms of mizoribine, an immunosuppressive imidazole nucleoside used clinically to inhibit rejection reactions after renal transplantation and in the treatment of systemic lupus erythematosus and rheumatoid arthritis, were studied in human and murine cells. We found that (a) human cells were 20- to 60-fold more resistant than murine cells to both mizoribine and its aglycone, (b) adenine phosphoribosyltransferase (APRT)-deficient human cells were resistant to aglycone but not to mizoribine, (c) hypoxanthine phosphoribosyltransferase (HPRT)-deficient human cells were at least 100-fold more sensitive to both mizoribine and aglycone, and (d) the decrease in intracellular GTP broadly paralleled the cytotoxicity in each case. Therefore, data obtained from studies using non-human tissues should be interpreted carefully before clinical application. Results indicate that the growth inhibitory effect of the aglycone but not of mizoribine is mediated by APRT, and depletion of guanine nucleotides is responsible for the effects of both drugs. Our data also suggest that the drugs may reduce mutant HPRT-deficient somatic cells in vivo, and may cause enhanced adverse reactions in HPRT-deficient individuals. The drug may have altered effects in patients receiving other purine or pyrimidine analogs.
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PMID:Differential cytotoxic effects of mizoribine and its aglycone on human and murine cells and on normal and enzyme-deficient human cells. 757 67

Chronic exposure of V79 cells to 80 daily doses of 150 J/M2, 290-330-nm ultraviolet light (UVB) produced a mixed cell population that was found to be generally more resistant to cell killing by both UVB and UVC (254 nm) than the wild-type cells. Several subclones from this population were studied for their survival and mutation responses and then one was chosen for further characterization based on this data. The studies carried out on this subclone, designated N806, show that its spontaneous HPRT mutation rate is approximately 10 times higher than that of wild-type V79 cells and it is almost three times more mutable than the wild-type cells when both are induced by UVB or UVC. The mutation responses of N806 and MI2G cells to 50-kVp X-rays are different, but the N806 cells do not appear to be hypermutable as they are with UV. N806 cells are also moderately more resistant to the cytotoxic effects of UV radiation but are more sensitive than MI2G cells when exposed to X-rays. Assays to measure the removal of cyclobutane pyrimidine dimers (CPDs) and the incision step of nucleotide excision repair have revealed no detectable difference in the repair capacities of N806 and parental V79 cells. These results suggest that chronic, protracted UV irradiation may be able to induce a 'mutator phenotype' in a subpopulation of the progenitor cells.
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PMID:Characterization of a mammalian cell line that exhibits spontaneous and ultraviolet light-induced hypermutability while retaining resistance to cell killing by ultraviolet light. 760 29

UV-induced cyclobutane pyrimidine dimers (CPD) are selectively removed from the transcribed strand of transcriptionally active genes in V79 Chinese hamster cells. This strand specificity of repair corresponds well with the observation that UV-induced mutations in the HPRT gene are primarily generated by DNA photolesions in the non-transcribed strand. This strand bias for mutations is, however, much more pronounced at 2 J/m2 than at the higher dose of 12 J/m2. An alternative explanation for strand specificity of mutations would be that most of the mutations are caused by pyrimidone 6-4 pyrimidine photoproducts (6-4 PP). Indeed experiments with a V79-derived cell line capable of repairing 6-4 PP but not CPD have revealed direct evidence for 6-4 PP as the mutagenic lesions in UV-irradiated hamster cells. This implies that 6-4 PP are also preferentially repaired in the transcribed strand. We have investigated the repair of DNA photolesions in the HPRT gene by measuring the distribution of bromodeoxyuridine-labeled repair patches in the transcribed and non-transcribed strands of genes employing a newly developed immunoextraction procedure. Three cell lines with different capacities to remove CPD and 6-4 PP from the HPRT gene and from the genome overall were used. We found no evidence for preferential repair of 6-4 PP in the transcribed strand of the HPRT gene in cells exposed to 10 J/m2. These data are in favor of a lack of strand-specific repair of 6-4 PP underlying the much less pronounced strand bias for induced mutations at high UV dose. However, the conclusive test would be the demonstration of preferential repair of 6-4 PP in the transcribed strand of transcriptionally active genes in cells exposed to 2 J/m2.
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PMID:UV-induced photolesions, their repair and mutations. 768 94

In this study we examined the metabolism of hypoxanthine in fibroblast growth factor (FGF)-stimulated porcine aortic endothelial cells (PAEC). Our previous report indicated that hypoxanthine in fetal bovine serum (FBS) was an essential component for both basal and FGF-dependent growth of PAEC (Hayashi et al., Exp Cell Res 185: 217-228, 1989). Besides hypoxanthine, the addition of various purine bases and purine nucleosides, but not xanthine, xanthosine or any pyrimidine metabolites, restored the limited growth of PAEC cultured in medium containing 10% dialyzed FBS in the presence or absence of FGF. The metabolism of [14C]hypoxanthine was compared in PAEC treated with and without FGF. Treatment of PAEC with FGF for 24 hr enhanced the radioactivity incorporation from [14C]hypoxanthine into both the acid-soluble and -insoluble fractions approximately 2-fold. Upon chromatographic analyses of hypoxanthine metabolites in the acid-soluble nucleotide fraction, it was found that in control PAEC hypoxanthine was largely metabolized to IMP, adenine nucleotides and uric acid, whereas in FGF-treated cells it was converted to ATP, ADP, GTP, xanthine and uric acid. The radioactivity of IMP was lowered in FGF-stimulated cells. The addition of FGF to PAEC increased phosphoribosyl pyrophosphate (PRPP) synthetase activity by approximately 8-fold and the PRPP content by approximately 2-fold, but it did not increase hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity or hypoxanthine transport. On the other hand, methotrexate, an inhibitor of de novo synthesis of purine, did not affect the growth of PAEC. Analyses of the rate of [14C]formate incorporation into total purine compounds showed that PAEC had a low capacity to synthesize purines de novo, which was not stimulated by FGF. These data indicate that FGF stimulates the synthesis of PRPP necessary for the salvage synthesis of purine nucleotides in conjunction with purine bases, e.g. hypoxanthine.
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PMID:Fibroblast growth factor-dependent metabolism of hypoxanthine via the salvage pathway for purine synthesis in porcine aortic endothelial cells. 768 70

Tiazofurin and ribavirin are clinically used inhibitors of IMP dehydrogenase (DH), binding to the NAD and IMP sites, respectively, of the target enzyme. In patients with chronic granulocytic leukemia in blast crisis, daily tiazofurin infusions decreased the high IMP DH activity in blast cells and resulted in 77% response (G. Weber. In: R. A. Harkness et al., Purine and Pyrimidine Metabolism in Man, Vol. VII, Part B, pp. 287-292, 1991). However, patients relapsed in a few weeks with emergence of high IMP DH activity (G. Tricot et al., Int. J. Cell Cloning, 8: 161-170, 1990). The present study showed that the tiazofurin-induced depression of IMP DH activity in rat bone marrow can be maintained by ribavirin injection. Tiazofurin (150 mg/kg, i.p., once a day for 2 days) decreased IMP DH activity to 10% and ribavirin (250 mg/kg, i.p., once a day for the subsequent 3 days) maintained the enzymic activity at 20 to 30% of control values. In control rats where no ribavirin was given, IMP DH activity of the tiazofurin-treated rats rapidly returned to the range of untreated animals. The decrease of IMP DH activity (t1/2 = 2.6 h) sharply preceded that of the bone marrow cellularity (t1/2 = 17.4 h). In addition to the target enzyme, IMP DH, tiazofurin also decreased activities of the guanylate metabolic enzymes, guanine phosphoribosyltransferase and GMP reductase, and the pyrimidine salvage enzymes, deoxycytidine and thymidine kinases with t1/2 of 2.6, 4.7, 6.0, 3.4, and 6.5 h, respectively. In cycloheximide-treated rats, where much of protein biosynthesis was blocked, the t1/2(8) of these five enzymes in bone marrow were shorter, 1.6, 4.3, 3.0, 0.6, and 0.8 h, respectively. Thus, the impact of tiazofurin in the bone marrow entails a decrease in the activity of the target enzyme, IMP DH, and also of other enzymes in purine and pyrimidine biosynthesis as a result of the enzyme half-lives shortened by this drug. These novel observations should assist in achieving better protection and recovery of bone marrow during and after chemotherapy.
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PMID:Sequential impact of tiazofurin and ribavirin on the enzymic program of the bone marrow. 790 99

The success of chemotherapy of colon tumours is currently limited. We have therefore used the human colon tumour cell line HT-29 to evaluate the cytotoxic effects of various drug combinations. Trimidox (3,4,5-trihydroxybenzamidoxime), a recently patented inhibitor of ribonucleotide reductase was combined with cytosinearabinoside (Ara-C) or 2',2'-difluorodeoxycytidine (DFDC) in order to inhibit both pyrimidine de novo and salvage pathways. Synergistic cytotoxic effects were observed. When HT-29 cells were sequentially treated with trimidox (20 microM for 24 h) and Ara-C (2 microM for 2 h), colony numbers decreased to 71% of the value calculated for additive cytotoxicity. When cells were simultaneously treated with trimidox (10 microM and 15 microM) and DFDC (0.2 nM), synergistic inhibition of colony formation was likewise noted (colony numbers decreased to values as low as 73% or 71% of the values calculated for additive cytotoxicity). On the other hand, we combined tiazofurin, an inhibitor of the guanylate de novo pathway, with allopurinol, which inhibits the guanylate salvage pathway by increasing intracellular hypoxanthine concentrations, leading to inhibition of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Synergistic cytotoxic effects were observed under these conditions too. When cells were treated with 10 microM tiazofurin and 400 microM or 800 microM allopurinol the number of colonies decreased to 69% and 27%, respectively, of the values calculated for additive effects. Our data suggest these drug combinations to be promising options in the treatment of human colon cancer.
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PMID:[Synergistic cytotoxic effects of chemotherapy in colon tumor cells by simultaneous inhibition of de novo and salvage energy metabolism pathways]. 794 93

(1) The currently used clinical anti-metabolites are targeted against-key enzymes of de novo purine and pyrimidine biosynthesis. However, the activities of salvage enzymes in each of the biosynthetic segments are markedly higher than those of the rate-limiting enzymes of de novo biosynthesis. Enzyme-pattern-targeted chemotherapy has been suggested to overcome the circumvention activity of salvage. Combination of inhibition of de novo and salvage pathways does provide a synergistic impact. Examples that enzyme-pattern-targeted drug treatment yields synergism include the following: tiazofurin (against IMP DH) and allopurinol (by raising serum hypoxanthine levels it inhibits GPRT); methotrexate or 5-FU lead to inhibition of the dTMP synthase reaction and AZT (a competitive inhibitor of thymidine kinase) or dipyridamole (a nucleoside transport inhibitor); acivicin, an inhibitor and inactivator of glutamine-utilizing enzymes in the de novo pathways of purine and pyrimidine biosynthesis, and dipyridamole. (2) Administration of MTX, 5-FU, tiazofurin or acivicin causes inhibition and/or inactivation of target enzymes. That these drugs are effective in spite of the presence of highly active salvage enzymes is now accounted for, at least in part, by new observations showing that these drugs markedly reduce (but do not eliminate) the activities (amounts) of CdR and TdR kinases, dTMP synthase and GPRT. This action is attributed to the rapid decay rate of these enzymes. (3) Studies on the bone marrow enzymic programs indicate that there is a window of opportunity for strengthening therapy and for the protection of bone marrow by administering salvage metabolites when the salvage enzymes are still present in high enough activities, i.e., 2-6 hr after administration of the blockers of de novo enzyme activities. (4) These results are a strong argument for discovering and utilizing inhibitors of purine and pyrimidine salvage enzymes to achieve more successful enzyme-pattern-targeted chemotherapy and to avoid development of resistant clones of cancer cells. (5) These approaches provide greater explanatory coherence than the previous accounts because recognition of (a) the importance of salvage and (b) rapid decay of key and salvage enzymes reveals a paradigm shift. The problem-solving process in chemotherapy should now be not only data-driven but also explanation-driven.
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PMID:Targeted and non-targeted actions of anti-cancer drugs. 794 86

Removal of UVB-induced cyclobutane pyrimidine dimers (CPD) from each of the two strands of the transcriptionally active p53 tumor suppressor gene and the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene was determined in the epidermis of the hairless mouse using the CPD-specific enzyme T4 endonuclease V. Mice were exposed to a single dose of UVB (2 kJ/m2) and kept in darkness for up to 24 h. About 80% of the CPD were removed from the transcribed strand of the p53 and HPRT genes within 24 h. Most rapid removal was observed during the first 4 h. In contrast, very little removal of CPD from the nontranscribed strand of the p53 and the HPRT genes was observed in 24 h. The same low level of repair was observed in the inactive c-mos proto-oncogene. The efficient repair of the transcribed strand compared to the nontranscribed strand of transcriptionally active genes in the epidermis of the hairless mouse resembles the repair of CPD in cultured rodent cells. Moreover, the selective removal of CPD from the transcribed strand of the p53 gene correlates well with the known strand bias of u.v.-induced mutations at dipyrimidine sites in the p53 gene of u.v.-induced mouse skin tumors.
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PMID:Strand-specific removal of cyclobutane pyrimidine dimers from the p53 gene in the epidermis of UVB-irradiated hairless mice. 797 Jul 1

Irradiation of cells with short wave ultraviolet light (UV-C) induces both cyclobutane pyrimidine dimers (CPD) as well as pyrimidine 6-4 pyrimidone photoproducts (6-4 PP). We have focused on the removal of both types of DNA photolesions from the transcriptionally active adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HPRT) genes and the inactive c-mos gene. Induction levels of both CPD and 6-4 PP were similar for all three genes analyzed, with the induction of 6-4 PP being about 3-fold lower than of CPD. Repair of CPD was analyzed using the CPD-specific enzyme T4 endonuclease V; repair of 6-4 PP was examined employing Escherichia coli UvrABC excinuclease. Unlike the HPRT gene, in which CPD were removed selectively from the transcribed strand, both strands of the 16-kilobase fragment encompassing the 2.6-kilobase APRT gene were repaired efficiently. This suggests the existence of multiple transcription units in the APRT region including transcription units running in the opposite direction of the APRT gene. Only a marginal part of the CPD was removed from the inactive c-mos gene after 24 h. In all three genes investigated, 6-4 PP were repaired more rapidly than CPD and, as demonstrated for the HPRT and APRT genes, without strand specificity. The difference in the repair phenotype of CPD between the HPRT gene and the APRT gene coincides with differences between both genes with regard to the DNA strand distribution of previously published UV-induced mutations.
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PMID:Analysis of repair of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts in transcriptionally active and inactive genes in Chinese hamster cells. 798 59


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