Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperthermia is under intensive investigation as a treatment for tumors both alone and in combination with other therapeutic agents. Hyperthermia has a profound effect on the function and structural integrity of tumor microvasculature; this has often been cited as a reason for its effectiveness in treatment of tumors. To test the role of hyperthermia in cytotoxic effects of active oxygen species, Chinese hamster, V79, and bovine endothelial cells were treated by the active oxygens, O not equal to 2 and H2O2, generated from the hypoxanthine/purine and xanthine oxidase reactions. It was found that cytotoxicity to V79 cells depends on the concentrations of purine and xanthine oxidase. A high level of cytotoxicity may be initiated in hyperthermia-treated tumors because high xanthine oxidase activity is known to be associated with tumors and endothelial cells, and degradation processes produce high concentrations of xanthine oxidase substrates in tumors. Since the cytotoxic effect can be reduced by the xanthine oxidase inhibitor, allopurinol, and the H2O2 removal enzyme, catalase, the cytotoxic effect in this experimental system is dependent on xanthine oxidase and H2O2. Adding erythrocytes at the same time as purine and xanthine oxidase could also prevent the cytotoxicity. Elevated temperatures stimulated the reaction of purine and xanthine oxidase and resulted in an increased cytotoxic effect. A similar effect is observed in growth inhibition and colony formation in endothelial cells without adding xanthine oxidase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperthermia enhances the cytotoxic effects of reactive oxygen species to Chinese hamster cells and bovine endothelial cells in vitro. 185 May 33

Cutaneous and mucous epithelia of various organs of laboratory rodents were analysed histochemically for reactive oxygen species (ROS)-generating oxidases using cerium methods. High activities of xanthine oxidase and also superoxide dismutase were present in orthokeratotic stratified squamous epithelia of skin, lips, esophagus and forestomach and parakeratotic keratinizing stratified epithelia of vagina, tongue and penis. Moreover, activity was found in simple epithelium of the uterus and intestine of rats, mice and guinea-pigs. Moderate activities of monoamine oxidase and D-amino acid oxidase were only seen in enterocytes of large and small intestine, whereas alpha-hydroxy acid oxidase could not be detected at all. With the use of specific inhibitors for superoxide anions-producing xanthine oxidase and H2O2-generating superoxide dismutase it was shown that epithelial cells of all studied external and internal surface epithelia contain a highly effective xanthine oxidase-superoxide dismutase system. It is hypothesized that this system might have a general microbicidal function and might play a special role in tumor promotion of the skin.
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PMID:Histochemistry of reactive oxygen-species (ROS)-generating oxidases in cutaneous and mucous epithelia of laboratory rodents with special reference to xanthine oxidase. 198 Sep 17

Skin tumor promotion induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) was inhibited by a concurrent and topical application of phthalic acid mono-n-butyl ester cupric salt (PAMBCu) in CD-1 mice initiated with 7,12-dimethylbenz[a]anthracene. PAMBCu inhibited TPA-caused epidermal ornithine decarboxylase (ODC) induction and ear edema formation, i.e. skin inflammation. However, neither PAMBCu nor superoxide dismutase (SOD) inhibited TPA-caused ODC induction in primary cultured mouse epidermal cells. 7-Bromomethylbenz[a]anthracene (BrMBA) is known to be a non-TPA type of tumor promoting agent. Epidermal ODC induction and inflammation caused by BrMBA were not inhibited by a concurrent application of PAMBCu. When mice were topically treated twice with PAMBCu, i.e. concurrently with and 7 h after BrMBA treatment, BrMBA-caused ODC induction was markedly suppressed. The same dose regimen of PAMBCu, however, failed to inhibit tumor promotion and inflammation caused by BrMBA. PAMBCu showed SOD-mimetic activity in superoxide generating systems, i.e. xanthine-xanthine oxidase reaction and TPA-stimulated polymorphonuclear leukocytes (PMN). Mono-n-butyl phthalate, which lacks SOD-mimetic activity, failed to inhibit TPA-caused ODC induction and skin inflammation. Therefore, inhibition by PAMBCu of TPA-caused tumor promotion, epidermal ODC induction and inflammation may be attributable to its SOD-mimetic activity. The results also support the contention that a superoxide anion of non-epidermal cell origin, such as PMN and macrophages, plays a role (probably some enhancing role) in in vivo ODC induction and tumor promotion caused by TPA. Failure of PAMBCu to inhibit BrMBA-caused tumor promotion suggests that superoxide anion generation is not involved in the tumor promoting action of this agent and that the anti-tumor promoting action of PAMBCu is dependent on the nature of the tumor promoting agents.
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PMID:Anti-tumor promoting action of phthalic acid mono-n-butyl ester cupric salt, a biomimetic superoxide dismutase. 211 May 12

The influence of dietary molybdenum on esophageal carcinogenesis induced by N-methyl-N-benzylnitrosamine (2.5 mg per kg of body weight once a week for 20 wk s.c.) was studied in male F344 rats. The tumor incidence and tumor development in the esophagus were significantly lower in the rats in the high-molybdenum (2 ppm) diet group than in the rats in the low-molybdenum (0.032 ppm) diet group; i.e., 44.4% (0.6 +/- 0.8) and 73.2% (2.2 +/- 2.0), respectively. The molybdenum levels in the esophagus-forestomach, liver, and serum were significantly higher in the high-molybdenum diet group than in the low-molybdenum diet group. Xanthine oxidase activity in the esophagus and forestomach in the high-molybdenum diet group was significantly higher than that in the low-molybdenum diet group, whereas liver and serum xanthine oxidase activities were not significantly different between these two groups. These results suggest that xanthine oxidase in the esophagus plays a significant role in the inhibitory effect of molybdenum on esophageal carcinogenesis.
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PMID:Effect of dietary molybdenum on esophageal carcinogenesis in rats induced by N-methyl-N-benzylnitrosamine. 231 26

Xanthine oxidase is most recognized for its role as the rate-limiting enzyme in nucleic acid degradation through which all purines are channelled for terminal oxidation. The enzyme serves as a source of oxygen-derived free radicals which induce both cellular injury and edema as well as changes in vascular permeability. In the study we compared xanthine oxidase levels of human brain tumors with normal brain tissues. Statistical evaluation of our results shows significantly higher xanthine oxidase levels in tumoral brain tissues. However, xanthine oxidase has not any significance for the differentiation of tumor types among each others. The oncotypes studied were meningioma and astrocytoma.
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PMID:Xanthine oxidase levels in human brain tumors. 232 31

Aldophosphamide, the penultimate cytotoxic metabolite of cyclophosphamide, can be detoxified by an oxidation reaction catalyzed by certain aldehyde dehydrogenases. The selective toxicity of cyclophosphamide is due, at least in part, to a greater expression of the relevant aldehyde dehydrogenase activity in normal cells relative to that expressed in certain tumor cells. Not known at the onset of this investigation was which of the several known mouse aldehyde dehydrogenases catalyze this reaction. Twelve enzymes that catalyze the NAD(P)-linked oxidation of aldophosphamide, acetaldehyde, benzaldehyde, and/or octanal were chromatographically resolved from mouse liver. Four of these appear to be novel; four others were determined to be betaine aldehyde dehydrogenase, succinic semialdehyde dehydrogenase, glutamic gamma-semialdehyde dehydrogenase, and xanthine oxidase (dehydrogenase). An additional aldehyde dehydrogenase, namely AHD-4, was semipurified from stomach. The stomach enzyme and nine of the hepatic enzymes catalyze the oxidation of aldophosphamide. Km values for these reactions range from 16 microM to 2.5 mM. The relevant aldehyde dehydrogenase of major importance varies with the tissue. In the liver, the major cytosolic aldehyde dehydrogenase, namely AHD-2, accounts for greater than 60% of total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) detoxification. Succinic semialdehyde dehydrogenase (AHD-12) and three of the novel hepatic aldehyde dehydrogenases, namely AHD-8, AHD-10, and AHD-13, also contribute significantly to total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide detoxification. In the stomach, AHD-4 and AHD-8 account for approximately 86% of total aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) detoxification. AHD-2 was not found in this tissue. Of all the aldehyde dehydrogenases examined, AHD-2 and AHD-8 were estimated to be the most efficient catalysts of aldophosphamide oxidation. Thus, these enzymes would seem most likely to be operative when tumor cells acquire aldehyde dehydrogenase-mediated cyclophosphamide resistance.
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PMID:Identification of the mouse aldehyde dehydrogenases important in aldophosphamide detoxification. 237 64

Recent evidence supports the concept that Adriamycin cytotoxicity may be mediated by drug semiquinone free radical and oxyradical generation. We tested this hypothesis further by exposing drug-sensitive (WT) and 500-fold Adriamycin-resistant MCF-7 human breast tumor cells (ADRR) to exogenous superoxide- and hydrogen peroxide-generating systems and subsequently monitored cell proliferation as a measure of cytotoxicity. The ADRR tumor cells tolerated a 4-fold greater exposure than sensitive cells to superoxide generated by the xanthine/xanthine oxidase system. Likewise, exposure to hydrogen peroxide produced by the action of glucose oxidase on glucose revealed a 4-fold diminished susceptibility of the drug-resistant cells to this reduced form of oxygen. Similar results were obtained by the direct application of hydrogen peroxide to cells. For both cell lines, cytotoxicity was dependent upon the magnitude and the duration of reactive oxygen exposure. When WT and ADRR cells were cultured under hyperoxia (95% O2:5% CO2), in order to stimulate the intracellular production of oxyradicals, proliferation was inhibited to a greater extent in the drug-sensitive cell line. Additionally, hyperoxia potentiated the cytotoxicity of Adriamycin to both sensitive and drug-resistant cells, but the effect depended upon the concentration of the drug. Under hyperoxic conditions, Adriamycin caused oxygen radical-dependent cytotoxicity to the WT tumor cells at clinically relevant drug concentrations as low as 2 to 3 nM. With ADRR tumor cells, hyperoxia increased the cytotoxicity of Adriamycin at concentrations above 5 microM. Paradoxically, both the WT and the ADRR tumor cells were equally susceptible to the cytotoxic effects of gamma irradiation. It is known that the Adriamycin-resistant MCF-7 cells greatly overexpress glutathione peroxidase and glutathione transferase activities; however, other biochemical defenses against reactive drug intermediates and oxygen radicals have been reported to be similar in the two cell lines. We have reexamined those observations in this report. The resistance of ADRR breast tumor cells to Adriamycin appears to be associated with a developed tolerance to superoxide, most likely because of a twofold increase in superoxide dismutase activity, and a decreased susceptibility to hydrogen peroxide, most likely because of 12-fold augmented selenium-dependent glutathione peroxidase activity. Acting in concert, these two enzymes would decrease the formation of hydroxyl radical from reduced molecular oxygen intermediates.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential oxygen radical susceptibility of adriamycin-sensitive and -resistant MCF-7 human breast tumor cells. 253 95

We have shown, in a preliminary report, that macrophages can induce strand breaks in the DNA of co-cultured tumor cells (Chong et al., 1988). The present study is designed to determine if oxygen-centered species generated by the cell-free enzyme-substrate combination of hypoxanthine and xanthine oxidase can induce similar lesions and to identify the specific mediator(s). We report that co-incubation of murine mammary tumor cell lines with hypoxanthine and xanthine oxidase leads to the induction of DNA-strand breaks as determined by fluorescence analysis of DNA unwinding (FADU) assay or alkaline elution techniques. This damage is preventable by catalase which removes hydrogen peroxide but no protection is provided by agents to remove or prevent the formation of superoxide anion (superoxide dismutase), or hydroxyl radical (mannitol or the iron chelator o-phenanthroline). Likewise, cyclooxygenase or lipoxygenase inhibitors of arachidonate metabolism (indomethacin, nordihydroguaiaretic acid, caffeic acid) or bromophenacyl bromide do not alter the degree of DNA scission. Treatment with higher doses of oxygen species leads to significant toxicity as determined by evaluation of cell growth potential or colony-forming ability. Again, toxicity is prevented only by the presence of catalase. Tumor cells are able to rejoin strand breaks at lower, less toxic doses. When comparing different tumor cell subpopulations at various stages of progression, i.e., metastatic vs. nonmetastatic, for sensitivity to hydrogen peroxide-induced strand breakage, we found that at lower concentrations (less than 5 microM) metastatic populations are sensitive whereas nonmetastatic populations exhibit no significant breakage. At higher concentrations of hydrogen peroxide, all lines were sensitive, suggesting that a lower threshold of sensitivity may exist for more progressed tumor cell lines.
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PMID:Reactive oxygen-mediated damage to murine mammary tumor cells. 255 50

The hypoxic cell cytotoxins SR 4233, benznidazole (Benzo), and CB 1954 were readily reduced by anaerobic mouse liver microsomes in vitro to their respective amino or single N-oxide derivatives. The reactions were inhibited in air and required reduced cofactors, particularly NADPH. The rates of reductive bioactivation were markedly different for each drug, with SR 4233 much greater than CB 1954 greater than Benzo. Using purified cytochrome P-450 reductase (P-450 reductase) and an inhibitory antibody to this enzyme, we demonstrated that P-450 reductase was involved in the reductive bioactivation of all 3 compounds. It had a minor role in SR 4233 reduction, but a more important involvement in CB 1954 metabolism to its 4-amino metabolite. Using carbon monoxide, a specific inhibitor of cytochrome P-450 (P-450), we demonstrated that P-450 was involved in both SR 4233 and Benzo reduction. P-450 had a major role both in SR 4233 conversion to SR 4317 and in the latter steps of Benzo amine formation. Purified xanthine oxidase was shown to reduce SR 4233 and Benzo in vitro, but cytosolic aldehyde oxidase activity was only detectable with Benzo as substrate. Characterizing the relative participation of the various reductases in tumor versus normal tissues may allow a more rational selection and application of hypoxic cell cytotoxins in cancer therapy.
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PMID:Molecular enzymology of the reductive bioactivation of hypoxic cell cytotoxins. 270 6

The passage of circulating tumor cells across vessel walls is an important step in cancer metastasis and is promoted by endothelial injury. Because Walker carcinosarcoma 256 (W256) cells generate oxygen-derived free radicals after cellular activation, the authors tested the hypothesis that these cancer cells can damage endothelial monolayers by producing such reactive oxygen species. To confirm that oxygen-derived radicals can damage endothelial cells, 3H-2-deoxyglucose-labeled human endothelial cell monolayers were exposed to xanthine oxidase in the presence of 0.2 mmol/l xanthine. 3H-2-deoxyglucose release was observed after the addition of xanthine oxidase in concentrations ranging from 6.5 x 10(-3) to 52 x 10(-3) units/ml. The extent of damage correlated with xanthine oxidase-dependent chemiluminescence (r = 0.91). Chemiluminescence assays in the presence of 5 x 10(-5) M luminol confirmed activation of the W256 cells by 1 x 10(-6) M chemotactic peptide fMLP. When fMLP-activated activated W256 cells were incubated with endothelial monolayers, concentrations of 2 x 10(6) to 6 x 10(6) W256 cells/ml were found to cause a 27% increase in the specific release of 2-deoxyglucose after a 90-minute incubation. A small but significant increase in 3H-2-deoxyglucose release also was observed in the absence of fMLP. Detection of 3H-2-deoxyglucose release in the presence of activated or unactivated tumor cells was dependent on preincubating the endothelial cell monolayer with 1 mM buthionine sulfoximine, an inhibitor of glutathione synthesis. Under these conditions, the specific release of 3H-2-deoxyglucose was increased from nondetectable levels to 21%, in the presence of 6.5 x 10(-3) units of the oxidase. Cultured W256 cells promoted isotope release from endothelial cell monolayers when activated with phorbol myristate acetate. Catalase (1000 units/ml) inhibited the tumor cell-induced release of 3H-2-deoxyglucose by 84% whereas superoxide dismutase, even at concentrations of 1 mg/ml, had no effect. A requirement for cell contact was shown because addition of cell-free supernatants from fMLP activated tumor cells did not cause 3H-2-deoxyglucose release and because pretreatment of W256 cells with 1 microM cytochalasin B inhibited their ability to promote isotope release even while increasing tumor cell-generated chemiluminescence threefold. Electron microscopy revealed that fewer cytochalasin B-treated W256 cells were attached to the endothelial cell monolayer than in untreated controls. It is concluded that the W256 tumor cells can damage endothelial cells directly via a mechanism involving production of reactive oxygen species.
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PMID:Walker carcinosarcoma cells damage endothelial cells by the generation of reactive oxygen species. 270 6


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