Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione peroxidases (GPX), enzymes that catalyze the reduction of reactive intermediates have been implicated in the action of several cytostatic drugs. Two major types of GPX have been found: a selenium-dependent form (SeGPX) which is active with both hydrogen peroxide and organic hydroperoxides, and a selenium-independent GPX which is only active with organic hydroperoxides. SeGPX and total GPX (tGPX) activity were assayed in cytosolic fractions from malignant and adjacent normal tissue in 13 patients with oral/oropharyngeal, and 10 patients with laryngeal squamous cell carcinoma. Neck lymph node metastases were available from 2 and 5 of these patient respectively. Tumors from the oral/oropharyngeal region contained significantly less SeGPX and tGPX activity than laryngeal tumors. Primary oral/oropharyngeal and laryngeal tumors had lower SeGPX activities than the matched normal mucosa. tGPX activities were similar in normal and tumor tissue. Metastases contained slightly more SeGPX and tGPX activity than the matched tumor tissue. We conclude that the inherent anti-tumor drug resistance of human neck squamous cell carcinoma is not mediated by increased glutathione peroxidase enzyme activity in the tumor tissue.
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PMID:Glutathione peroxidases in human head and neck cancer. 761 Aug 35

Fe-NTA is a known renal carcinogen. However, little is known about its carcinogenic potential in liver. In this study we for the first time show that Fe-NTA is a potent hepatic tumor promoter. Fe-NTA administration induced dose dependently the hepatic ornithine decarboxylase (ODC) activity several folds as compared to its activity in the saline-treated rats. Similarly, hepatic DNA synthesis which is measured as [3H]thymidine incorporation in DNA is also increased following Fe-NTA treatment. The effects of Fe-NTA were similar to other tumor promoters not only with respect to inducing ODC activity and [3H]thymidine incorporation in DNA but also in depleting antioxidant armory of the tissue. Fe-NTA depleted levels of glutathione to about 35% of the saline-treated control and activities of antioxidant enzymes catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase decreased significantly (45-55% of saline-treated control). Concomitant with the depletion in antioxidant armory, Fe-NTA augmented hepatic microsomal lipid peroxidation more than three folds. The pretreatment of rats with antioxidants BHA or BHT diminished the observed effects of Fe-NTA. Our data indicate that Fe-NTA is a potent hepatic tumor promoter and acts through a mechanism involving oxidative stress.
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PMID:Ferric nitrilotriacetate (Fe-NTA) is a potent hepatic tumor promoter and acts through the generation of oxidative stress. 762 70

A very potent competitive inhibitor of mammalian glyoxalase II activity, N,S-bis-fluorenylmethoxycarbonylglutathione (DiFMOC-G) has been synthesized and characterized. The Ki value for inhibition of glyoxalase II purified from calf liver is 0.08 microM. The Ki values for glyoxalase I inhibitions range from 285 to 500 fold higher than the values obtained for glyoxalase II inhibitions, depending on the source of the enzyme. Among other enzymes involved in glutathione metabolism, such as glutathione S-transferase, glutathione reductase, and glutathione peroxidase, only glutathione S-transferase is inhibited to a small extent by DiFMOC-G. Diesters of DiFMOC-G were prepared in order to improve transport of DiFMOC-G into mammalian tumor cells (rat adrenal pheochromocytoma, PC-12) in culture. Among the diesters synthesized, diisopropyl DiFMOC-G was found to be the most inhibitory to cell viability, with a [I]0.5 value of 3 microM.
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PMID:N,S-bis-fluorenylmethoxycarbonylglutathione: a new, very potent inhibitor of mammalian glyoxalase II. 762 27

In this study, the activity of the glutathione related enzymes, namely glutathione S-transferase (GST), glutathione reductase (GSSG-R), Selenium-dependent and -independent glutathione peroxidase (GPX) of various TGC tumors (n = 18) obtained from untreated patients, was compared to that of the corresponding enzymes of normal testicular tissues (n = 5). The enzymes of all tumorous tissues except teratomas were significantly less active, than the corresponding enzymes of nontumorous tissues. The GST was in seminomas 4.3-20-, in embryonal carcinomas 47-, and in mixed tumors 13-47-fold less active than in the normal testes. The GST activity of teratomas was about half of that of the normal tissues. The Se-independent GPX, component of GST alfa class, comprised about 90 percent of the total GPX activity in normal testis; however it was absent or barely detectable in all TGC tumors except teratomas. The latter had about the same GPX activity as the tumor-free testicular tissues. Apart from the teratoma, the GSSG-R activity of all TGC tumors was also suppressed to about one third of that of the normal testis. The insufficient function of glutathione related enzymes of TGC tumors may contribute to their sensitivity against treatment. The poorer prognosis of teratomas, however, may be explained by the relatively higher activity of their detoxifying enzymes.
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PMID:Glutathione related enzymes in human testicular germ cell tumors and normal testes. 765 23

Aerobic cells have several scavenger systems for protection from reactive oxygen species (ROS). We developed an ROS-resistant variant of the human erythroleukemic cell line K562 by culturing cells in glucose oxidase to produce hydrogen peroxide. Testing the activity of the scavenger systems for ROS showed these cells had a 25- to 28-fold increase in catalase activity. We therefore termed this variant cell line K562-CAT. There was no similar increase in glutathione content or activity of superoxide dismutase and glutathione peroxidase. To determine what effect the increased catalase activity would have on the immune response to these tumor cells, we compared K562 and K562-CAT sensitivity to tumor necrosis factor-alpha (TNF alpha) activated polymorphonuclear neutrophil (PMN), natural killer (NK), and lymphokine-activated killer (LAK) cells. K562-CAT showed a significant increase in resistance to TNF alpha-activated PMN but not to NK or LAK, confirming the role of ROS in the former but not the latter. We also tested K562-CAT sensitivity to cisplatin and mitomycin C, agents known to involve ROS in their cytotoxic mechanism. There was no increased resistance in K562-CAT compared to parental K562, indicating that catalase is not involved in tumor cell resistance to those drugs. Given the characteristics of its resistance to the immune response, K562-CAT or a similar catalase-hyperexpressing cell line could be useful in determining the significance of TNF alpha-activated PMN in antitumor defenses.
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PMID:Characterization of an oxidation-resistant tumor cell line and its sensitivity to immune response and chemotherapy. 774 66

The ability of human cells to regenerate ascorbic acid from dehydroascorbate is partially dependent on the glutathione redox status of the cell and the relative activity of dehydroascorbate reductases. Mammalian dehydroascorbate reductase activity is associated with two proteins known as thioltransferase (glutaredoxin) and protein disulfide isomerase. We compared the specific activity of thioltransferase, protein disulfide isomerase, and other GSH-related enzymes in Adriamycin-resistant human breast tumor cells, MCF-7 ADRR, and Adriamycin-sensitive, MCF-7 WT, tumor cells. MCF-7 ADRR cells had higher activities of glutathione peroxidase (34.7 fold), nonseleno-glutathione peroxidase (glutathione S-transferases; 5.3 fold), thioredoxin (2.3 fold), and thioltransferase (4.0 fold) compared with the WT Adriamycin-sensitive cell line. Thioltransferase was detected in Western blots in extracts of ADRR MCF-7 cells but not in WT MCF-7 cells. alpha-Tocopherol in the membrane and cytosolic fractions was 2.8 and 3.0 fold higher, respectively, in Adriamycin-resistant compared with Adriamycin-sensitive cells. Supplementation of MCF-7 cells with L-ascorbic acid 2-phosphate (2 and 10 mM) had no effect on WT cell viability after 5 days incubation with up to 0.33 microM Adriamycin. In contrast, supplementation of ADRR MCF-7 cells with L-ascorbic acid 2-phosphate resulted in enhanced resistance up to 3.4 microM Adriamycin over a 5-day incubation. Both lines of MCF-7 cells demonstrated the ability to utilize ascorbic acid as the 2-phosphate derivative. After 48 h incubation with 8.6 microM Adriamycin, the resistant cells maintained normal viability and ascorbate-dehydroascorbate levels, whereas drug-sensitive cells had significantly lower ascorbate with a higher percent dehydroascorbate and increased cell death as judged by cell protein levels (52% of controls).
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PMID:Ascorbic acid and cell survival of adriamycin resistant and sensitive MCF-7 breast tumor cells. 775 Jul 94

Alpha-linolenic acid (ALA) and eicosapentaenoic acid (EPA) exhibited potent cytotoxic action on SP 2/0 mouse myeloma cells in vitro. Both SOD and vitamin E could inhibit the action of ALA and EPA indicating a role for reactive oxygen species and lipid peroxides. In addition, both ALA and EPA enhanced the formation of superoxide anion, hydrogen peroxide and lipid peroxides, and caused a reduction in the levels of antioxidant enzymes: SOD, catalase and glutathione peroxidase and induced significant damage to DNA in SP 2/0 cells. Thus, ALA and EPA inhibit antioxidant defenses of the cell and damage the DNA, which can ultimately lead to tumor cell lysis.
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PMID:Free radical-dependent suppression of growth of mouse myeloma cells by alpha-linolenic and eicosapentaenoic acids in vitro. 775 58

Antioxidants and reactive oxygen species are considered to play an important role in experimental in vivo carcinogenesis studies. We attempted in this study to evaluate the repercussions on the antioxidant and lipid peroxide status of the growth of human malignant tumors xenografted into athymic mice. We selected three tumor models: two urothelial carcinomas (bladder tumors stage 3) and one brain tumor (glioblastoma stage 4). All these tumors exhibited a fast growth pattern when xenografted into athymic mice. Tumoral tissue was implanted subcutaneously. After growth establishment each tumor size was measured at regular intervals: every 2 d for bladder tumor and twice a week for glioblastoma. The period of observation was 3 wk for bladder tumors and 5 wk for glioblastoma. At the end of the observation period, all mice were sacrificed; tumoral tissue was taken and blood collected. Superoxide dismutase activity (SOD), glutathione peroxidase activity (GSH-Px), zinc (Zn), selenium (Se), and thiobarbituric acid reactive substances (TBARS) were measured in blood. TBARS alone were measured into tumoral tissue. A modification of the antioxidant blood status was observed in mice xenografted with bladder tumors with decrease in Se status and GSH-Px activities, and increase in TBARS. Such an effect was absent in mice xenografted with glioblastoma. It would appear that an oxygen-mediated stress exists in the animal bearing an implanted tumor compared with the control group, and that tumoral tissue itself is able to induce an oxidative stress into its host. All this leads to a disturbance of the antioxidant defense system.
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PMID:Antioxidant status and lipid peroxidation in athymic mice xenografted with two types of human tumors. 777 35

Murine leukemia L1210 cells rendered deficient in glutathione peroxidase (GPX) and phospholipid hydroperoxide glutathione peroxidase (PHGPX) by Se deprivation (L.Se(-) cells) were found to be more sensitive to tert-butyl hydroperoxide (t-BuOOH) cytotoxicity than Se-replete controls (L.Se(+) cells). Human K562 cells, which express PHGPX, but not GPX, were also more sensitive to t-BuOOH in the Se-deficient (K.Se(-)) than Se-satisfied (K.Se(+)) condition. In examining the metabolic basis for selenoperoxidase-dependent resistance, we found that glucose-replete Se(-) cells reduce t-BuOOH to t-butanol far more slowly than Se(+) cells, the ratio of the first-order rate constants approximating that of the GPX activities (L1210 cells) or PHGPX activities (K562 cells). Monitoring peroxide-induced changes in GSH and GSSG gave consistent results; e.g., glucose-depleted L.Se(+) cells exhibited a first order loss of GSH that was substantially faster than that of glucose-depleted L.Se(-) cells. Under the conditions used, peroxide-induced conversion of GSH to GSSG could be stoichiometrically reversed by resupplying D-glucose, indicating that no significant lysis or GSSG efflux and/or interchange had taken place. The apparent first-order rate constant for GSH decay increased progressively for L1210 cells expressing a range of GPX activities from approximately 5% to 100%, demonstrating that peroxide detoxification is strictly dependent on enzyme content. The initial rate of 14CO2 release from D-[1-14C]glucose supplied in the medium was much greater for L.Se(+) or K.Se(+) cells than for their respective Se(-) counterparts, consistent with greater hexose monophosphate shunt activity in the former. These results highlight the importance of selenoperoxidase action in the glutathione cycle as a means by which tumor cells cope with hydroperoxide stress.
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PMID:Selenoperoxidase-dependent glutathione cycle activity in peroxide-challenged leukemia cells. 777 66

Aldehyde dehydrogenase (ALDH) is well known for its involvement in the resistance of tumor cells to cyclophosphamide (CPA) and its activated derivatives, such as 4-hydroperoxy-CPA (4HC). The role of other drug-metabolizing enzymes such as glutathione S-transferase (GST) in CPA resistance is, however, less certain. In the present study of a human breast cancer cell line (MCF-7) exhibiting about 6-fold resistance to 4HC (MCF/HC), cellular levels of glutathione (GSH) were increased 1.4-fold, while cytosolic GST and ALDH activities were increased 2.7- and 7.2-fold, respectively, relative to the MCF-7 parental line. No significant changes in glutathione peroxidase and NADPH cytochrome P450 reductase activity, and no increase in microsomal GST and GST pi mRNAs were found in the resistant cells. Treatment with the ALDH substrate octanal sensitized the cells to the cytotoxic effects of 4HC to a modest extent in both MCF-7 and MCF/HC cells [dose modification factor (DMF) of 1.4 and 1.6, respectively]. Depletion of GSH by treatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) enhanced the cytotoxic effect of 4HC to a similar extent in both cell lines. By contrast, ethacrynic acid, which inhibited GST activity by > 85% in MCF-7 and MCF/HC cell extracts without depletion of GSH, sensitized the resistant but not the parental cells to 4HC cytotoxicity, indicating the importance of GST as a determinant of 4HC resistance in these cells. This conclusion is supported by the observation that in MCF/HC cells, ethacrynic acid in combination with BSO increased the DMF 3-fold higher than did BSO or EA alone, while in the parental MCF-7 cells ethacrynic acid with BSO had no significant chemosensitization effect over BSO alone. These studies establish that in addition to ALDH, GST overexpression can contribute to acquired resistance of tumor cells to 4HC and, furthermore, suggest that modulators that target the GSH/GST system could be useful in overcoming CPA resistance in the clinic.
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PMID:Identification of glutathione S-transferase as a determinant of 4-hydroperoxycyclophosphamide resistance in human breast cancer cells. 778 10


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