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)

In the present study we have compared the levels of glutathione (GSH) S-transferase, GSH peroxidase and GSH reductase in human breast tumors and adjacent normal tissues obtained from the same individuals. We have also quantitated GST pi type antigen in these samples by western blotting. GST pi activity towards 1-chloro-2,4-dinitrobenzene was found to be elevated in tumors from three out of six patients (patient nos. 2, 4 and 5), whereas this activity was suppressed in tumor from patient no. 1. Results of Western blotting using antibodies raised against GST pi of human placenta were in agreement with the GST activity data. GSH peroxidase activity with cumene hydroperoxide as substrate was found to be elevated in four tumor samples (patient nos. 2, 4, 5, and 6) but suppressed in tumor from patient no. 1. On the other hand, GSH reductase activity was elevated in three samples (patients nos. 2, 4 and 5) and downregulated in the remaining three samples (patients nos. 1, 3 and 6). These results indicate that GSH-related enzymes are differentially altered in human breast tumors and GST pi type isoenzyme(s), unlike certain other human carcinomas such as colonic, are not uniformly elevated in human breast tumors.
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PMID:Differential expression of glutathione S-transferase, glutathione peroxidase and glutathione reductase in normal and malignant human breast tissues. 233 97

The effect of selenium intake on the development of pancreatic cancer was investigated in female Syrian golden hamsters. Four-week-old hamsters were divided into 2 groups according to the selenium level in their drinking water and were fed a purified diet containing less than 0.05 ppm selenium. Starting 4 weeks later, groups received 10 s.c. injections at weekly intervals of N'-nitrosobis(2-oxopropyl)amine (BOP) dissolved in saline, while controls received saline alone. When the animals were killed 18 weeks after the last injection, palpable tumors were less frequent in the high-selenium group than in animals receiving low-selenium supplement, the numbers of histologically diagnosed cancerous lesions also being significantly reduced by high selenium intake. The selenium level and glutathione peroxidase activity in serum and pancreas were significantly greater in the high-selenium group. Moreover, selenium levels and glutathione peroxidase activity were both significantly higher in tumor-bearing tissue. The results suggest that glutathione peroxidase is involved as an intermediate factor in prevention of carcinogenesis by selenium.
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PMID:Inhibitory effect of selenium on hamster pancreatic cancer induction by N'-nitrosobis(2-oxopropyl)amine. 236 2

A large number of human tumor cell lines of various origins have been investigated with respect to expression of glutathione-linked enzymes in the cytosol fraction. The amounts of the different enzymes were estimated by use of activity measurements and by silver staining or immunoblot analysis after electrophoresis of cytosol fractions purified by affinity chromatography on S-hexylglutathione Sepharose. Class Pi glutathione transferase was the most abundant enzyme in most tumor cells; the cell lines HepG2 and Raji were exceptions in not expressing significant amounts of this enzyme. HepG2 cells derive from hepatocytes, which normally do not express the class Pi enzyme, whereas Raji cells originate from B-lymphocytes, which normally do express a class Pi glutathione transferase. The highest level of the class Pi transferase, in terms of protein reacting with antibodies as well as enzyme activity, was noted in the colon carcinoma cell line LS174T. Hu549Pat cells, EBV-transformed B-lymphocytes, also expressed high levels of a protein reacting with antibodies specific for class Pi glutathione transferases, but did not display any significant activity with ethacrynic acid, a substrate characteristic for this class. Class Alpha and class Mu glutathione transferases, in cell lines expressing these isoenzymes, were present in significantly lower concentrations than the class Pi enzyme. Most of the tumor cells contained a class Alpha transferase composed of 27.5 kd subunits, which has the physicochemical and immunological properties of the most basic glutathione transferase found in human skin. In several cell lines, a protein was detected with an apparent subunit Mr value of 30 kd that was tentatively identified as an additional class Alpha glutathione transferase not previously described. In addition, other glutathione-linked enzyme activities, namely glutathione peroxidase, glutathione reductase and glyoxalase I, were assayed with specific substrates in the cytosolic fraction of the tumor cells; glyoxalase I could also be estimated semiquantitatively by silver staining of SDS-PAGE cells after affinity chromatography. Like the glutathione transferases, these enzymes displayed distinctly different levels of expression in the various cell lines. Thus, virtually every cell line was found to have a unique pattern of glutathione-linked enzymes, suggesting that the resistance phenotypes of the cells differ accordingly.
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PMID:Differences among human tumor cell lines in the expression of glutathione transferases and other glutathione-linked enzymes. 240 Oct 46

We examined whether the cause of the remarkable decreases in the activities of lipid peroxidation-preventive enzymes in the heart of adriamycin (ADR)-treated mice might be related to inhibition of DNA, RNA or protein biosynthesis. It was found that biosyntheses of DNA, RNA and protein in the heart, liver and kidney of mice were markedly inhibited by ADR (15 mg/kg, ip). The inhibitory effects of ADR on each type of biosynthesis were particularly marked in the heart among the tissues examined. Strong correlations between the percentage inhibition of DNA and protein biosynthesis by ADR, and the percentage decrease in the activities of lipid peroxidation-preventive enzymes were observed in the heart, liver, kidney and lung, especially for the decrease of glutathione peroxidase activity and the inhibition of DNA and protein biosyntheses. We also found that marked decreases of DNA, RNA and protein biosynthesis in ADR-treated mice occurred not only in the heart but also in tumor tissues. From these results, we conclude that the increment of cardiac lipid peroxide in ADR-treated mice, which is closely related to the cardiotoxicity of ADR, results from inhibition of DNA, RNA and protein biosyntheses after the distribution of ADR.
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PMID:Effect of adriamycin on DNA, RNA and protein biosyntheses in mouse tissues, in connection with its cardiotoxicity. 248 82

The enzymes that utilize H2O2 and lipoperoxides as well as the enzymes of the bioregeneration system glutathione and NADP+ have been examined for activity in the superficial and deep regions of DMBA-induced rat fibrosarcoma and the adjoining skeletal muscle. The activities shown by catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and glucoso-6-phosphate dehydrogenase were 2-3 times higher and reduced glutathione levels were lower in the superficial than in deep areas. The high antioxidant potential of the tumor superficial areas is proposed to be due to the oxygen-dependent mechanisms by which macrophages and neutrophils select tumor cell clones by the given sign.
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PMID:[High activity of antioxidant enzymes in a tumor as a factor of "avoidance of control" in the immune system]. 249 12

The effects of selenium intake on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis were examined in rats fed a diet high in mixed fats and representative of that consumed in North America. Six groups of 20 rats were fed an AIN-76 diet modified to contain 20% fat from lard:corn oil (3:1 wt/wt) and various amounts of selenium (0.1, 0.035, 0.1, 1.0, 2.0 or 4.0 mg Se/kg diet). At wk 5, animals in groups 2-6 were dosed with 4.32 mg of DMBA. Serum clinical parameters and the activities of plasma selenium-dependent and total glutathione peroxidase (GSHPx), erythrocyte GSHPx and superoxide dismutase (SOD) were determined every 4 wk for 25 wk. The extent of lipid peroxidation was determined by measuring urinary malondialdehyde during wk 13 and 24, and erythrocyte malondialdehyde at wk 25. Erythrocyte GSHPx was found to be a better indicator of selenium status than plasma activity, while SOD did not vary with dietary selenium. The group of animals fed 4.0 mg Se/kg diet had reduced numbers of tumors (P less than 0.01), but this reduction was associated with evidence of chronic selenium toxicity. Variations in GSHPx activity with dietary selenium did not result in differences in tumor incidence, nor in changes in lipid peroxidation in the other groups. Thus, nontoxic levels of selenium do not appear to offer any protective effect during carcinogenesis in rats fed a casein-based diet similar in fat content to that consumed by North Americans.
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PMID:Effects of dietary selenium on DMBA-induced carcinogenesis in rats fed a diet high in mixed fats. 249 71

Female weanling Sprague-Dawley rats were used to examine the changes that occurred in selenium and antioxidant status during the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. Animals were fed an AIN-76 diet, modified to contain 20% fat (3:1 wt/wt, lard:corn oil) and 0.1, 0.035, 0.1, 1.0, 2.0 or 4.0 mg Se/kg diet. At wk 5, rats in groups 2-6 were administered by intragastric tube 4.32 mg of DMBA dissolved in corn oil. Control rats received corn oil only. A blood sample was removed from the tail vein and analyzed for selenium-dependent glutathione peroxidase (Se-GSHPx) and superoxide dismutase (SOD) activity at wk 5, and every 4 wk until wk 25. At the end of the experiment, rats were classified by tumor status, and each diet group was subdivided into two groups: those rats remaining free of tumors for 25 wk and those with tumors. DMBA treatment caused an initial decrease in erythrocyte SeGSHPx and SOD activity compared to untreated control rats. SeGSHPx activity in rats with tumors remained lower than controls, while SeGSHPX activity increased in rats with no tumors. These changes, however, were not associated with any changes in lipid peroxidation.
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PMID:Changes in selenium and antioxidant status during DMBA-induced mammary carcinogenesis in rats. 249 72

The ability of cells to detoxify lipid hydroperoxides (LOOHs) generated by hematoporphyrin derivative (HPD)-sensitized photooxidation was investigated for the first time. The general importance of glutathione in cytoprotection was confirmed by showing that murine L1210 cells were more sensitive to the lethal effects of HPD plus red light after being treated with buthionine sulfoximine. The specific role of Se-dependent glutathione peroxidase was investigated by using L1210 cells that were grown in Se-deficient media. Glutathione peroxidase activity of such cells was typically less than 5% of that exhibited by Se-replete cells. When examined by means of dye exclusion or clonogenic assay, Se-deficient cells were dramatically more sensitive to HPD-mediated photokilling than normal counterparts. Impaired metabolism of hydrogen peroxide was ruled out as a possible cause of enhanced photokilling, since added catalase had no protective effect on Se-deficient cells. Iodometric analysis of lipid extracts from photooxidized cells indicated a significantly greater rate of LOOH accumulation as a result of Se depletion. Moreover, when depleted cells were incubated in the dark after a short period of photo-peroxidation, LOOH decay was markedly slower than in controls. Similar results were obtained with human CaSki cells derived from cervical carcinoma. It is apparent from these results that lipid peroxidation plays an important role in tumor cell eradication by HPD/phototherapy, and that glutathione peroxidase serves as a natural protectant against photokilling by catalyzing the reduction of LOOHs.
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PMID:Role of lipid peroxidation in hematoporphyrin derivative-sensitized photokilling of tumor cells: protective effects of glutathione peroxidase. 252 45

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

Resistance to antineoplastic drugs is a major problem in the clinical management of cancer. Previous studies have demonstrated that the cytotoxicity of certain anticancer drugs is increased by lowering the glutathione (GSH) levels with buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase. In this study we report that the resistance to doxorubicin, an anthracycline antibiotic and the most active agent in the treatment of breast cancer, can be partially reversed by exposing MCF-7 doxorubicin-resistant breast tumor cells (MCF-7/ADRR) to minimally cytotoxic doses of BSO. We found that the BSO treatment (50 microM, 48 h) of MCF-7/ADRR cells resulted in 80 to 90% depletion in total GSH concentrations. The toxicity of doxorubicin, as determined by growth inhibition and clonogenic assays, was significantly potentiated in the BSO-treated GSH-depleted cells relative to control breast tumor cells, and a dose-modifying factor of 5 to 7 was observed. Since the cytotoxicity of doxorubicin has been associated with its ability to undergo enzymatic activation and to form hydroxyl (OH) radicals in this cell line, we also quantitated the OH formation in the BSO-treated and untreated MCF-7/ADRR cells using electron spin resonance spintrapping techniques. These results show that doxorubicin stimulated at least 2-fold more OH formation in the tumor cells after GSH levels were decreased by 90%. These results indicate that GSH plays an important role in modulating doxorubicin-induced OH formation via the scavenging of hydrogen peroxide by glutathione peroxidase and thus partially protects MCF-7/ADRR cells from the cytotoxic effect of doxorubicin.
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PMID:Potentiation of doxorubicin cytotoxicity by buthionine sulfoximine in multidrug-resistant human breast tumor cells. 253 60


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