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)

Even moderate variations of the extracellular cysteine concentration were previously shown to affect T cell functions in vitro despite high concentrations of cystine. We therefore analyzed the membrane transport activities of T cells for cysteine and cystine, and the role of low molecular weight thiol in T cell-mediated host responses against a T cell tumor in vivo. A series of T cell clones and tumors including the highly malignant lymphoma L5178Y ESb and its strongly immunogenic variant ESb-D was found to express extremely weak transport activity for cystine but strong transport activity for cysteine. However, not all cells showed the expected requirement for cysteine (or 2-mercaptoethanol (2-ME)) in the culture medium. One group of clones and tumors including the malignant ESb-lymphoma did not respond to changes of extracellular cystine concentrations and was strongly thiol dependent. This group released only little acid soluble thiol (cysteine) if grown in cystine-containing cultures. The other T cell lines, in contrast, were able to maintain high intracellular GSH levels and DNA synthesis activity in cystine-containing culture medium without cystein or 2-ME and released substantial amounts of thiol. This group included the immunogenic ESb-D line. Additional thiol-releasing ESb variants were obtained by culturing large numbers of L5178Y ESb tumor cells in cultures without cysteine or 2-ME. All of these ESb variants showed a significantly decreased tumorigenicity and some of them induced cytotoxic and protective host responses even against the malignant ESb parent tumor. Taken together, our experiments suggest that the host response against a tumor may be limited in certain cases by the failure of the stimulator (i.e., the tumor) cell to deliver sufficient amounts of cysteine to the responding T cells.
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PMID:Expression of increased immunogenicity by thiol-releasing tumor variants. 154 66

Acquired resistance to cis-platinum and melphalan, in the human ovarian OAW42 tumor cell line, respectively, conferred a 3- and 1.5-fold decrease in photon sensitivity. Analysis of cell survival curves by the linear quadratic equation showed an accompanying 5- and 2-fold reduction in the magnitude of the initial slope (alpha). Treatment with the GSH depleting agent BSO restored the magnitude of alpha to a value similar to that of the parental line without evidence of dose modification in the high-dose region of the cell survival curve. This in conjunction with failure of alteration in GSH levels to affect parental OAW2 sensitivity and of the SER of BSO to reflect GSH levels suggest a possible GSH independent mechanism of action for BSO. If similar patterns occur in the clinic, the possibility exists of circumventing collateral resistance between chemotherapeutic agents and ionizing radiation, provided that tumor thiol levels can be preferentially depleted.
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PMID:BSO-induced reduction of glutathione levels increases the cellular radiosensitivity of drug-resistant human tumor cells. 154 51

MRA-CN, the alkylating cyanomorpholino derivative of doxorubicin (DOX), is extremely potent (100 to 1000 fold increase in cytotoxicity in vitro and in vivo), more lipophilic, non-cardiotoxic, and non-cross-resistant in multidrug resistant cells compared to DOX. We have developed an ovarian carcinoma cell line ES-2R that is 4-fold resistant to MRA-CN, compared to the parental ES-2 cells. This resistant cell line exhibits cross-resistance to alkylators and ionizing radiation. Glutathione (GSH) and GSH-dependent enzymes were found to be altered in the resistant cells with 1.5-fold increase in GSH, and 2- to 3-fold increase in the pi-class glutathione-s-transferase (GST) protein. Both D,L buthionine-S,R-sulfoximine (BSO) and ethacrynic acid (EA), inhibitors of GSH biosynthesis and pi-class GST activity, respectively, could sensitize the ES-2R cells to MRA-CN. These findings implicate a role for GSH metabolism in resistance of ES-2R cells to MRA-CN. The data also indicates the potential utility of EA to modulate GST activity and sensitize tumor cells toward alkylators.
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PMID:Sensitization of drug resistant human ovarian cancer cells to cyanomorpholino doxorubicin (MRA-CN) by modulation of glutathione metabolism. 154 57

The effects of glutamine-enriched total parenteral nutrition (TPN+GLN) were studied in tumor-bearing rats because glutamine can benefit host tissues but also may stimulate tumor growth. Rats were implanted with the methylcholanthrene-induced fibrosarcoma (MCA sarcoma) and were studied when the tumor constituted less than 5% of carcass weight (small tumor) and when the tumor constituted 10% of carcass weight (large tumor). Provision of 20% of TPN protein as glutamine produced a significant increase in the arterial glutamine level and maintained the skeletal muscle intracellular glutamine concentration (2.02 +/- 0.1 versus 1.39 +/- 0.07 mumol/g, p less than 0.01). Concurrently, hindquarter GLN fractional release increased nearly threefold (p less than 0.05) in the TPN+GLN group. Glutamine-enriched total parenteral nutrition did not affect carcass weight, tumor weight, tumor DNA content, or tumor glutaminase activity. Furthermore, DNA flow cytometric analysis did not demonstrate any difference in percentage of aneuploid tumor cells within the G1, S, or G2M cell cycles. However, the ratio of aneuploid to diploid cells within the tumor mass increased by 20% in animals receiving glutamine. Glutamine-enriched total parenteral nutrition had no effect on tumor glutathione (GSH) levels. No increase in hepatic GSH levels was observed, but gut mucosal GSH levels were 20% greater in the TPN+GLN group (p less than 0.05). The provision of glutamine-enriched TPN may be beneficial to the host by maintaining skeletal muscle glutamine stores and by supporting gut GSH biosynthesis. In this tumor model, TPN+GLN does not appear to increase tumor size, tumor DNA content, or tumor glutamine metabolism, but the ratio of tumor cells to host infiltrating cells within the tumor mass appears to be increased.
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PMID:The effects of glutamine-enriched total parenteral nutrition on tumor growth and host tissues. 154 96

Many furan-containing natural products that induce increased activity of the glutathione S-transferase (GST) enzyme system have been found to inhibit tumorigenesis in laboratory animals. 2-n-Heptylfuran (HF) and 2-n-butylthiophene (BT), a sulfur analogue of furan, are two of the many furans and thiophenes formed during the roasting process of meat. BT and HF, when administered by gavage at doses that ranged from 11 to 90 mumol, induced increased GST activity in various tissues of A/J mice. At 90 mumol/dose, BT induced increased GST in the liver, small bowel mucosa, and lung. No increase in enzyme activity was found in the forestomach. HF was an enzyme inducer in the liver, small bowel mucosa, and forestomach but was inactive in the lung. The acid-soluble sulfhydryl level, a good measure of glutathione contents in tissues, was examined in tissue homogenates from mice treated with BT and HF. BT induced significant increase of GSH in the liver and lung at the higher doses. No change was observed in either the small bowel mucosa or the forestomach. A 50-mumol dose of HF was found to increase GSH level in all four tissues studied. The inhibition of lung and forestomach tumorigenesis was carried out with A/J mice using benzo[a]pyrene as the carcinogen. BT treatment resulted in a reduction of tumor multiplicity in the lung and forestomach. The tumor incidence in the forestomach was reduced significantly. The potency of HF as inhibitor of carcinogenesis was similar to that of BT in the forestomach of mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory effects of 2-n-heptylfuran and 2-n-butylthiophene on benzo[a]pyrene-induced lung and forestomach tumorigenesis in A/J mice. 157 41

The anticarcinogenic effect of dietary turmeric on benzo[a]pyrene-(BP) induced forestomach neoplasia and 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumorigenesis in female Swiss mice was evaluated. To further elucidate the mechanism of antineoplastic action of turmeric, its effect on the hepatic cytochrome b5, cytochrome P-450, glutathione, and glutathione S-transferase activities was studied in female Swiss mice. Turmeric (2% or 5%) in the diet significantly inhibited the BP-induced forestomach tumors, and this response was dose and time dependent. The 2% turmeric diet significantly suppressed DMBA-induced skin tumors in mice. The 5% turmeric diet for seven consecutive days resulted in a 38% decrease in the hepatic cytochrome b5 and cytochrome P-450 levels. Glutathione content was increased by 12%, and the glutathione S-transferase activity was enhanced by 32% in the liver. Our results document a protective effect of turmeric on BP-induced forestomach and DMBA-induced skin tumors in mice.
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PMID:Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice. 157 46

The alkylating anticancer drugs, mechlorethamine (HN2), chlorambucil, cyclophosphamide, carmustine and lomustine readily induced cytotoxicity in isolated rat hepatocytes. Hepatocyte glutathione (GSH) was depleted rapidly following addition of the drugs. Lipid peroxidation ensued following GSH depletion and before cytotoxicity occurred. Furthermore, cytotoxicity was delayed by the antioxidants butylated hydroxyanisole (BHA) and alpha-tocopherol, the ferric iron chelator desferoxamine or the radical trap 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) even when added 10 min later. HN2 was much less toxic to hepatocytes under nitrogen and caused much less lipid peroxidation than under aerobic conditions. Cytotoxicity induced by HN2 was also prevented by choline, suggesting that a choline carrier is responsible for HN2 uptake in the hepatocytes. Various sulfur compounds acted as antidotes for HN2 cytotoxicity. Thiosulfate was still effective when added 30 min after HN2. Depletion of GSH in the hepatocytes markedly increased their susceptibility to HN2. However, BHA, desferoxamine or TEMPO protected these hepatocytes from HN2. This suggests that antioxidants could prove useful in preventing the increased risk of hepatotoxicity if GSH-depleting agents are used to overcome tumor resistance to nitrogen mustards.
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PMID:Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation. 159 84

The exact mechanism by which carcinogens and tumor promoters act on the glucocorticoid receptor system in vivo is not known. Based on earlier studies that sulfhydryl-reducing agents stabilize glucocorticoid receptor binding in vitro, some workers have postulated that endogenous reducing factors may be important for glucocorticoid receptor function in vivo. To test whether glutathione (GSH) may serve this purpose, we investigated the effects of phorone, an agent that partially depletes intracellular GSH, on the hepatic cytosolic glucocorticoid receptor (GRc) binding characteristics in intact and 7-10 day adrenalectomized (ADX) adult female Sprague-Dawley rats. Biochemical analysis revealed that a single treatment of phorone (300 mg/kg) to both intact and ADX rats significantly decreased the liver GSH concentration (70-90% of control levels) as well as the GRc maximum binding concentration (30% of control levels). The decrease in GSH levels preceded the reduction in GRc maximum binding concentrations; both effects were reversible after 24 h of treatment. The phorone-mediated decrease of GSH levels was maximum at doses greater than 75 mg/kg, whereas GRc maximum binding concentrations in vivo appeared dose dependent up to 400 mg/kg. Pretreatment with phorone or the carcinogens mirex and 3-methylcholanthrene significantly decreases GRc binding and nuclear uptake in vivo, as well as diminishes intracellular cytosolic GSH levels. Although a temporal relationship between the GSH levels and the GRc maximum binding concentrations in vivo was observed, there was no quantitative relationship between these two parameters based on our phorone dose-response and the carcinogen pretreatment data. Our findings suggest that during the early phases of carcinogenesis, the hepatocellular GSH does not play a direct role upon the biochemical action of certain carcinogens and tumor promoters on the glucocorticoid receptor binding in the liver.
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PMID:Phorone (diisopropylidene acetone), a glutathione depletor, decreases rat glucocorticoid receptor binding in vivo. 163 71

We have used an enzymatic (spectro-photometric) and a flow cytometric (GSH-MBCL) method to compare the glutathione (GSH) content of doxorubicin sensitive (P388) and resistant (P388/R-84) murine leukemic and human lung cancer cells. The flow cytometric analysis revealed that GSH-MBCL conjugate formation was dependent on glutathione-S-transferase (GST) activity. The human solid tumor cell lines exhibited extensive heterogeneity, high GSH content, and GST activity. In contrast to the enzymatic method, the flow cytometric method did not accurately reflect the 95% reduction in GSH content of cells treated for 24 h with 100 microM BSO. Possible reaction of MBCL with other sulfhydryl groups (other than GSH) in BSO-treated cells may be responsible for this discordance. We have also shown the feasibility of using dual parameter flow cytometry to monitor cellular anthracycline (daunorubicin) retention and GSH-MBCL conjugate fluorescence in human tumor cells. These two parameters, which measure drug retention and cellular detoxification, are believed to be the important determinants of chemoresistance in tumor cells.
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PMID:Flow cytometric monitoring of glutathione content and anthracycline retention in tumor cells. 164 68

Groups of rats, either dosed with N-nitrosodiethylamine (NDEA) for 10 weeks (from the age of 7 to 17 weeks) or untreated, were fed diets containing either 2% (low fat, LF) or 30% polyunsaturated fat (high fat, HF) on an equicaloric basis from 5 weeks until rats were 43 weeks old. Biochemical parameters were measured during and at the end of the experiment in various organs, blood, urine and exhaled air, for correlation with the presence or absence of tumors. The HF diet tended to increase the number of hepatic tumors induced by NDEA, while the number of extrahepatic tumors was higher in rats fed on the LF diet; also the overall tumor incidence was higher in the LF group. In the HF/NDEA group, only two benign extrahepatic tumors were found. Plasma total and free cholesterol and triglyceride concentrations were lower in the HF than the LF group without NDEA treatment. In animals bearing liver and/or extrahepatic tumors all plasma lipid concentrations were lower than in tumor-free animals. Only minor or no changes were detected in blood catalase activity, malondialdehyde level, reduced glutathione (GSH) level or GSH-related enzymes and excretion of thioethers in the urine due to dietary modulation or NDEA. Changes in the liver that were associated with the HF diet were: (i) increased amounts of some polyunsaturated fatty acids and of total phospholipids in liver microsomes; (ii) an enhanced level of lipid peroxidation in liver; (iii) a decrease in liver glutathione levels during NDEA treatment, with a simultaneous adaptive increase in superoxide dismutase levels, and a decrease in renal glutathione levels in both treated and untreated groups; (iv) enhanced microsomal induction of aminopyrine N-demethylase and epoxide hydrolase activities by NDEA, and (v) decreased hexose monophosphate shunt (HMS) activity. All mono-oxygenase activities were lower, and the activities of epoxide hydrolase, UDP-glucuronosyltransferase and HMS were higher, in liver tumors than in non-tumorous liver of similarly-treated rats. Neither diet nor NDEA had a major effect on drug-metabolizing enzyme activities in lung and kidney. HF diet significantly increased ethane exhalation (an indicator of the whole-body pro-oxidant state) over those on the LF diet: in rats on either diet, it was further increased when NDEA was given. Ethane exhalation was still elevated 30 weeks after the cessation of NDEA treatment. Our results suggest an association between the observed changes in biochemical parameters, notably oxidative stress, due to dietary modulation and the altered tumor incidence and organ distribution of tumors induced by NDEA.
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PMID:Mechanisms of fat-related modulation of N-nitrosodiethylamine-induced tumors in rats: organ distribution, blood lipids, enzymes and pro-oxidant state. 167 40


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