Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have characterized the effects of phorbol myristate acetate (PMA) on human monocyte and neutrophil oxidative metabolism and antibody-dependent cytotoxicity toward anti-D sensitized human erythrocytes (RBC) and a human lymphoblastoid cell line (CEM). Hexose monophosphate shunt activity was measured by [1-(14)C]glucose oxidation and target lysis by (51)Cr release. PMA produced a dose-dependent stimulation of hexose monophosphate shunt activity. Neutrophils responded with higher hexose monophosphate shunt activity and at a lower PMA concentration than did monocytes. PMA increased monocyte lysis of antibody-sensitized RBC by two-thirds, but did not affect lysis of CEM targets. Neutrophils were unable to lyse either antibody-sensitized or nonsensitized RBC without the addition of PMA. When PMA was added, lysis of both targets increased markedly. Neutrophils without PMA were able to lyse a small number of both antibody-sensitized and nonsensitized CEM targets. PMA also increased neutrophil lysis of these targets. Target lysis by neutrophils from a patient with chronic granulomatous disease, cells unable to produce reactive oxygen species, was not increased by PMA. Chronic granulomatous disease monocytes, however, responded to PMA by more than doubling lysis of antibody-sensitized RBC. Hypoxia inhibited PMA augmentation of antibody-sensitized RBC lysis by neutrophils, but not by monocytes. Generation of reactive oxygen species by the xanthine-xanthine oxidase system inhibited CEM growth, but did not cause lysis, indicating that in some cases oxidative injury may be nonlytic. We suggest that PMA augments neutrophil cytotoxicity to tumor and RBC targets by stimulating reactive oxygen species-mediated lysis, but in monocytes augmentation of lysis is due to activation of a nonoxidative mechanism of lysis.
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PMID:Activation of monocyte and granulocyte antibody-dependent cytotoxicity by phorbol myristate acetate. 706 17

Using the human erythroleukaemic cell line K562 cl.6 and its daunorubicin-resistant subline K/DAU600, and the human T-lymphoblastic leukaemic cell line CCRF-CEM and its vinblastine-resistant subline CEM/VLB100, we have shown that the drug-resistant cell lines were more sensitive to cytotoxicity induced by tumour necrosis factor-alpha (TNF alpha). Drug-resistant cell lines showed increased activities of copper/zinc superoxide dismutase (Cu/ZnSOD) and catalase compared with their parental drug-sensitive cell lines. However, the greater susceptibility of drug-resistant cells to TNF alpha cytotoxicity was, in part, related to their decreased activities of manganese superoxide dismutase (MnSOD). Persistence of this differential sensitivity when MnSOD is inhibited by sodium nitroprusside (SNP) suggests that the greater susceptibility of drug-resistant cells to TNF alpha was not entirely due to their decreased level of MnSOD activity. K562 cl.6 and K/DAU600, which were more resistant to TNF alpha, both expressed greater levels of endogenous plasma membrane-bound TNF alpha than the CCRF-CEM cell line. All cell lines examined were (more or less) equal in susceptibility to the cytolytic effect of exogenous O2-. generated by xanthine/xanthine oxidase. These results demonstrate that both MnSOD and endogenous TNF alpha play a role in protecting leukaemic cells against TNF alpha cytotoxicity, but there is an unknown mechanism that causes drug-resistant cells to be more susceptible to TNF alpha cytotoxicity.
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PMID:TNF-mediated killing of human leukaemic cells: effects of endogenous antioxidant levels and TNF alpha expression in leukaemic cell lines. 770 80

Methotrexate, an important agent in the treatment of childhood acute lymphoblastic leukaemia, has generally failed to induce dose-dependent cytotoxicity of patient-derived leukaemic blasts when tested in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. This effect is apparently due to salvage from the medium, by surviving leukaemic cells, of metabolites such as hypoxanthine and thymidine. In an attempt to address this problem, we have examined the effect, on leukaemic cell populations, of enzymatically depleting these metabolites from the culture medium employed during the MTT assay, using xanthine oxidase and thymidine phosphorylase. Specifically we have assessed methotrexate cytotoxicity in the paediatric acute lymphoblastic T cell leukaemia, GKTL, which is maintained as a xenograft, and like primary leukaemias, has poor viability in vitro. Although little cytotoxicity of GKTL cells was observed when the MTT assay was performed in supplemented RPMI-1640 medium, dose-dependent cytotoxicity of these cells was clearly apparent when the same medium was enzymatically depleted. In contrast, the ID50 for methotrexate of control CCRF-CEM cells was unaltered in enzymatically depleted medium. In the absence of methotrexate, enzymatic depletion of the medium did not affect leukaemic cell survival. We are currently investigating the general applicability of this approach for assaying the response to methotrexate of primary leukaemia samples.
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PMID:Methotrexate cytotoxicity determination using the MTT assay following enzymatic depletion of thymidine and hypoxanthine. 844 66

The level of systemic exposure to 2',3'-dideoxyinosine (ddI) is increased 40 to 300% when it is coadministered with allopurinol (Allo), ganciclovir (GCV), or tenofovir. However, the mechanism for these drug interactions remains undefined. A metabolic route for ddI clearance is its breakdown by purine nucleoside phosphorylase (PNP). Consistent with previous reports, enzymatic inhibition assays showed that acyclic nucleotide analogs can inhibit the phosphorolysis of inosine. It was further established that the mono- and diphosphate forms of tenofovir were inhibitors of PNP-dependent degradation of ddI (K(i)s, 38 nM and 1.3 microM, respectively). Allo and its metabolites were found to be relatively weak inhibitors of PNP (K(i)s, >100 microM). Coadministration of tenofovir, GCV, or Allo decreased the amounts of intracellular ddI breakdown products in CEM cells, while they increased the ddI concentrations (twofold increase with each drug at approximately 20 microM). While inhibition of the physiological function of PNP is unlikely due to the ubiquitous presence of high levels of enzymatic activity, phosphorylated metabolites of GCV and tenofovir may cause the increased level of exposure to ddI by direct inhibition of its phosphorolysis by PNP. The discrepancy between the cellular activity of Allo and the weak enzyme inhibition by Allo and its metabolites may be explained by an indirect mechanism of PNP inhibition. This mechanism may be facilitated by the unfavorable equilibrium of PNP and the buildup of one of its products (hypoxanthine) through the inhibition of xanthine oxidase by Allo. These findings support the inhibition of PNP-dependent ddI degradation as the molecular mechanism of these drug interactions.
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PMID:Role of purine nucleoside phosphorylase in interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir, or tenofovir. 1504 6