Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress has been suggested to play an integral role in the cancer process. It may be particularly significant during tumor progression, where there is likely to be a large amount of free radicals generated by infiltrating inflammatory cells and dying tumor cells. In order to test this hypothesis, a variety of free radical scavengers and antioxidants were assessed for their ability to inhibit tumor progression. The murine skin multistage carcinogenesis model was used to generate papillomas, which are a population of putative precancerous lesions. Various test agents were applied topically to papillomas in order to determine if they would decrease the incidence of the malignant lesion, squamous cell carcinoma. The agents tested included: reduced glutathione (GSH), butylated hydroxyanisole, vitamin E, copper(II) (3,5-diisopropylsalicylate)2, sodium benzoate, N-acetyl cysteine and disulfiram. Under the conditions of our experiments, only GSH and disulfiram inhibited tumor progression to a significant degree. Additional studies indicated that GSH prevented cancer development in a dose-dependent manner. Another experiment demonstrated that when papillomas received repeated topical applications of diethylmaleate, a GSH-depleting agent, tumor progression was enhanced. Collectively these data suggest that sufficient glutathione levels may be important in preventing cancer formation.
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PMID:Effect of exogenous glutathione on tumor progression in the murine skin multistage carcinogenesis model. 313 44

The differential levels of induction of hepatic microsomal cytochrome P-450 (cyt. P-450), UDP-glucuronyl transferase (UDPGT) and cytosolic glutathione-S-transferase (GST) activities were evaluated over various periods of time, following tumor transplantation in male Swiss albino mice in the presence and absence of beta-carotene supplementation in their basal diet (100 mg/kg). An increase in the total hepatic microsomal cytochrome P-450 and UDP-glucuronyl transferase and cytosolic GSH-transferase activities (1.5 to 2 fold) occurred during the later stage of tumor progression (22 +/- 2 days onwards). However, beta-carotene supplementation throughout the study increased or decreased the random activity trends of the above markers significantly (P < 0.05- < 0.01). Finally, beta-carotene supplementation could enhance the survival of the host bearing lymphoma by almost 2-fold (50-60 days) over and above the lymphoma controls (30-35 days).
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PMID:Role of beta-carotene on the changes in activity patterns and levels of biotransforming enzymes in transplantable murine lymphoma. 773 55

IL-2 therapy can induce marked oxidative stress via reactive oxygen and nitrogen intermediates. Glutathione, the major intracellular reductant, may become rate limiting to cytotoxic lymphocyte activation and proliferation under these circumstances. N-Acetyl cysteine (NAc-cys) was used to increase intracellular glutathione levels during lymphokine-activated killer (LAK) cell activation by IL-2. Incubation of splenocytes with NAc-cys (0.6 to 1.0 mM) resulted in significant changes in intracellular reduced and total glutathione (92% and 58% increase, respectively) at 96 h. These levels correlated with markedly enhanced cell proliferation (threefold) and cytolytic effector cell generation (> fivefold increase in LU/10(6) cells) induced by the combination of NAc-cys with IL-2. IL-2 exposure by itself unexpectedly increased intracellular reduced glutathione by 43%. IL-2 and NAc-cys were synergistic in increasing glutathione levels (reduced glutathione: 292% increase; total: 251% increase). Inhibition of glutathione synthesis, using L-buthionine-(S,R)-sulfoximine reversed the effects of NAc-cys on intracellular glutathione, as well as cellular proliferation and cytotoxicity. This experiment established that the effects of NAc-cys required de novo glutathione synthesis. In conjunction with IL-2/LAK treatment, oral NAc-cys administration (260 to 900 mg/kg/day for 7 days) significantly decreased tumor progression in a refractory s.c. tumor model. A small fraction of mice (11 to 17%) had complete tumor regressions. NAc-cys may be useful as an adjunct to increase the antitumor activity of IL-2/LAK therapy.
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PMID:Use of N-acetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2. 820 9

Gamma-glutamyltranspeptidase (GGT), a plasma membrane-bound enzyme, provides the only activity capable to effect the hydrolysis of extracellular glutathione (GSH), thus favoring the cellular utilization of its constituent amino acids. Recent studies have shown however that in the presence of chelated iron prooxidant species can be originated during GGT-mediated metabolism of GSH, and that a process of lipid peroxidation can be started eventually in suitable lipid substrates. The present study was undertaken to verify if a GGT-dependent lipid peroxidation process can be induced in the lipids of biological membranes, including living cells, and if this effect can be sustained by the GGT highly expressed at the surface of HepG2 human hepatoma cells. In rat liver microsomes (chosen as model membrane lipid substrate) exposed to GSH and ADP-chelated iron, the addition of GGT caused a marked stimulation of lipid peroxidation, which was further enhanced by the addition of the GGT co-substrate glycyl-glycine. The same was observed in primary cultures of isolated rat hepatocytes, where the lipid peroxidation process did not induce acute toxic effects. GGT-stimulation of lipid peroxidation was dependent both on the concentration of GSH and of ADP-chelated iron. In GGT-rich HepG2 human hepatoma cells, the exposure to GSH, glycyl-glycine, and ADP-chelated iron resulted in a nontoxic lipid peroxidation process, which could be prevented by means of GGT inhibitors such as acivicin and the serine-boric acid complex. In addition, by co-incubation of HepG2 cells with rat liver microsomes, it was observed that the GGT owned by HepG2 cells can act extracellularly, as a stimulant on the GSH- and iron-dependent lipid peroxidation of microsomes. The data reported indicate that the lipid peroxidation of liver microsomes and of living cells can be stimulated by the GGT-mediated metabolism of GSH. Due to the well established interactions of lipid peroxidation products with cell proliferation, the phenomenon may bear particular significance in the carcinogenic process, where a relationship between the expression of GGT and tumor progression has been envisaged.
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PMID:gamma-Glutamyl transpeptidase-dependent lipid peroxidation in isolated hepatocytes and HepG2 hepatoma cells. 911 54

The relationship among cancer growth, the glutathione redox cycle and the antioxidant system was studied in blood and in tumour cells. During cancer growth, the glutathione redox status (GSH/GSSG) decreases in blood of Ehrlich ascites tumour-bearing mice. This effect is mainly due to an increase in GSSG levels. Two reasons may explain the increase in blood GSSG: (a) the increase in peroxide production by the tumour that, in addition to changes affecting the glutathione-related and the antioxidant enzyme activities, can lead to GSH oxidation within the red blood cells; and (b) an increase of GSSG release from different tissues into the blood. GSH and peroxide levels are higher in the tumour cells when they proliferate actively, however GSSG levels remain constant during tumour growth in mice. These changes associate with low levels of lipid peroxidation in plasma, blood and the tumour cells. The GSH/GSSG ratio in blood also decreases in patients bearing breast or colon cancers and, as it occurs in tumour-bearing mice, this change associates with higher GSSG levels, especially in advanced stages of cancer progression. Our results indicate that determination of glutathione status and oxidative stress-related parameters in blood may help to orientate cancer therapy in humans.
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PMID:Changes in glutathione status and the antioxidant system in blood and in cancer cells associate with tumour growth in vivo. 989 33

The expression of gamma-glutamyl transpeptidase (GGT), a plasma membrane ectoenzyme involved in the metabolism of extracellular reduced glutathione (GSH), is a marker of neoplastic progression in several experimental models, and occurs in a number of human malignant neoplasms and their metastases. Because it favors the supply of precursors for the synthesis of GSH, GGT expression has been interpreted as a member in cellular antioxidant defense systems. However, thiol metabolites generated at the cell surface during GGT activity can induce prooxidant reactions, leading to production of free radical oxidant species. The present study was designed to characterize the prooxidant reactions occurring during GGT ectoactivity, and their possible effects on the thiol redox status of proteins of the cell surface. Results indicate that: (i) in U937 cells, expressing significant amounts of membrane-bound GGT, GGT-mediated metabolism of GSH is coupled with the extracellular production of hydrogen peroxide; (ii) GGT activity also results in decreased levels of protein thiols at the cell surface; (iii) GGT-dependent decrease in protein thiols is due to sulfhydryl oxidation and protein S-thiolation reactions; and (iv) GGT irreversible inhibition by acivicin is sufficient to produce an increase of protein thiols at the cell surface. Membrane receptors and transcription factors have been shown to possess critical thiols involved in the transduction of proliferative signals. Furthermore, it was suggested that S-thiolation of cellular proteins may represent a mechanism for protection of vulnerable thiols against irreversible damage by prooxidant agents. Thus, the findings reported here provide additional explanations for the envisaged role played by membrane-bound GGT activity in the proliferative attitude of malignant cells and their resistance to prooxidant drugs and radiation therapy.
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PMID:Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation. 1049 Feb 84

Reactive oxygen species (ROS), represented by superoxide, hydrogen peroxide and hydroxyl radicals, have been implicated in many diseases including cancer. ROS have been known to play an important role in the initiation and promotion of multistep carcinogenesis. The cellular antioxidants play a crucial role in protection against neoplastic disease. However, very little is known about the antioxidant defense in cervical carcinoma. This is addressed in the present study. Lipid peroxides, glutathione content and the activities of antioxidant enzymes, together with vitamin C and E content, were estimated in patients who had carcinoma of the cervix, and the values were compared with those of normal women. The results showed a remarkable reduction in the content of glutathione, vitamin E and C. Activities of glutathione peroxidase and superoxide dismutase were also reduced in cervical cancer compared to normal controls (P < 0.001). This reduction was more marked in late stages (III, IV) than in early stages (I, II) (P < 0.001). Glutathione was reduced more in poorly differentiated tumors (grade III) than in well and moderately differentiated ones (grade I, II) (P < 0.05). Levels of lipid peroxides were found to be significantly higher in malignant than in normal tissue samples and their levels were correlated with advanced clinical stage (P < 0.001). Our results suggest impaired antioxidant status in carcinoma of the cervix. This impairment is related to tumor progression.
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PMID:Lipid peroxidation and antioxidant status in human cervical carcinoma. 1068 51

Carotenoids of dietary origin have recently been the subject of renewed research interest because of epidemiological evidence indicating an inverse relationship between intake of carotenoids-rich plant substances and risk of certain cancers. This study was attempted to understand the biological actions of dietary beta-carotene (BC) on Dalton's lymphoma (DL), a rapidly proliferating transplantable tumor, in effecting the survival of the lymphoma-bearing mice. The glutathione (GSH) level and the extent of lipid peroxidation in the liver, kidney and brain were monitored in BC-treated (100 mg/kg food) mice transplanted with DL. These markers showed substantial alterations during the whole length of tumor progression in lymphoma-bearing mice without BC supplementation. When treated with BC, both malondialdehyde contents (evidence of lipid peroxidation) and the GSH levels in different organs were found to be closer to normal values in the initial period of tumor progression. BC-mediated protection against lipid peroxidation was maximally found to be in hepatic tissue throughout the study following DL transplantation. This was fairly reflected in the higher BC concentration in hepatic tissue of BC-treated lymphoma group compared to untreated lymphoma control. Significantly higher survival time (51-55 days) was observed in BC-treated animals in comparison to their untreated DL counterparts (35-38 days). The prolonged survival observed in the BC-supplemented animals may be attributed to the higher resistance offered by animals receiving BC towards lipid peroxidation-related tissue injury.
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PMID:Beta-carotene prolongs survival, decreases lipid peroxidation and enhances glutathione status in transplantable murine lymphoma. 1083 19

Gamma-glutamylcysteine synthetase (gamma-GCS) is a heterodimer consisting of heavy (gamma-GCSh) and light (gamma-GCSl) subunits. gamma-GCS catalyzes the rate-limiting de novo biosynthesis of glutathione (GSH), an abundant physiological antioxidant that plays important roles for regulating oxidative stress. Expression of gamma-GCSh and gamma-GCSl are sensitive to oxidative stress. To investigate whether expression of gamma-GCS is correlated with tumor progression, we used immunohistochemical approaches to examine 16 human colorectal adenomas and resected 57 carcinomas from untreated patients. In adjacent normal colorectal epithelium, levels of gamma-GCSh expression were low. Strong cytoplasmic staining for gamma-GCSh was detected in 3 (18.8%) adenoma and 48 (84.2%) carcinomas. The frequency of gamma-GCSh expression in carcinoma was significantly higher than in adenoma (p<0.0001). We used RNase protation assay and Western blot to determine levels of gamma-GCSh mRNA and protein from 10 pairs of matched carcinomas with adjacent normal controls. Elevated expression of both gamma-GCSh mRNA and protein were found in 6 cases, suggesting that transcriptional and/or posttranscriptional regulation play an important role in the upregulation of gamma-GCS during colorectal carcinogenesis. We also examined the expression of another redox-regulated gene, multidrug resistance protein 1 (MRP1). Strong staining for MRP1 was detected in 1 (6.3%) adenoma and 40 (70.2%) carcinomas. The frequency of MRP1 expression in carcinoma was significantly higher than in adenoma ( p<0.0001). Nuclear p53 expression was detected in 30 (52.6%) of carcinomas. There is a significant correlation between gamma-GCSh and MRP1 expression (p=0.013) but not between gamma-GCSh and p53. Since gamma-GCS is a sensor of oxidative stress, these results are consistent with the notion that oxidative stress is associated with colorectal tumor progression.
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PMID:Expression of heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCSh) in human colorectal carcinoma. 1177 39

Cancer development results from the interaction between genetic factors, the environment, and dietary factors have been identified as modulators of carcinogenesis process. The formation of DNA adducts is recognized as the initial step in chemical carcinogenesis. Accordingly, blocking DNA adducts formation would be the first line of defense against cancer caused by carcinogens. Glutathione-S-transferases inactivate chemical carcinogens into less toxic or inactive metabolite through reduction of DNA adducts formation. There are many different types of glutathione S-transferase isozymes. For example, GST delta serves as a marker for hepatotoxicity in rodent system, and also plays an important role in carcinogen detoxification. Therefore, inhibition of GST activity might potentiate the deleterious effects of many environmental toxicants and carcinogens. In addition, approximately half of the population lacks GST Mu expression. Epidemiological evidence showed that persons possessing this genotype are predisposed to a number of cancers including breast, prostate, liver and colon cancers. In addition, individual risk of cancer depends on the frequency of mutational events in target oncogenes and tumor suppressor genes which could lead to loss of chromosomal materials and tumor progression. The most frequent genetic alteration in a variety of human malignant tumors is the mutation of the coding sequence of the p53 tumor suppressor gene. O(6)-alkylguanine in DNA leads to very high rates of G:C deltaA:T transitions in p53 gene. These alterations will modulate the expression of p53 gene and consequently change DNA repair, cell division, and cell death by apoptosis. Also, changes in the expression of BcI-2 gene results in extended viability of cells by over-riding programmed cell death (apoptosis) induced under various conditions. The prolonged life-span increases the risk of acquiring genetic changes resulting in malignant transformation. In addition, a huge variety of food ingredients have been shown to affect cell proliferation rates. They, therefore, may either reduce or increase the risk of cancer development and progression. For example, it has been found that a high intake of dietary fat accelerates the development of breast cancer in animal models. Certain diets have been suggested to act as tumor promoters also in other types of cancer such as colon cancer, where high intake of fat and phosphate have been linked to colonic hyper-proliferation and colon cancer development. Different factors such as oncogenes, aromatic amines, alkylating agents, and diet have a significant role in cancer induction. Determination of glutathione S-transferase isozymes in plasma or serum could be used as a biomarker for cancer in different organs and could give an early detection.
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PMID:Cancer and phase II drug-metabolizing enzymes. 1257 Jul 45


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