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 S-transferases (GSTs) are enzymes involved in the detoxification of xenobiotics and are divided into four subclasses, alpha, mu, pi, and theta, with different although overlapping substrate specificities. Most human gastrointestinal tumors contain increased amounts of GST-pi and GST enzyme activity. The relationship between GST parameters and tumor and patient characteristics, including overall survival, were studied retrospectively in 100 primary colorectal adenocarcinomas. Levels of GST-alpha, GST-mu, GST-pi, and GST enzyme activity were not related to the Dukes stage, differentiation grade, localization, histological type and diameter of the tumor, or gender and age of the patient. Fifty-seven patients died (median survival, 21 months; range, 1-65 months) during follow-up, and 43 patients were still alive at the closing date of the study (median follow-up, 68 months; range, 60-87 months). Optimal dichotomization and uni- and multivariate analyses were done with the Cox proportional hazard model. Multivariate analysis with all clinicopathological parameters revealed higher Dukes stage (hazard ratio, 2.7; P < 0.001) and older age (hazard ratio, 2.8; P = 0.001) to be the only independent prognostic variables for overall survival. In contrast to GST-alpha and GST-mu, high levels of GST-pi (hazard ratio, 3.1; P = 0.002) and GST enzyme activity (hazard ratio, 2.0; P = 0.020) in the tumors were found to have a significant prognostic value independent from the clinicopathological parameters when added separately to this Cox model. Thus, this study indicates that GST subclass levels in colorectal adenocarcinomas are not related to clinicopathological parameters and that the GST-pi level and GST enzyme activity have a prognostic value for the overall survival of the patients.
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PMID:Glutathione S-transferase pi in colorectal tumors is predictive for overall survival. 778 Sep 87

Cyclophosphamide (CX) has been widely used as an anticancer agent, however obtaining a maximum therapeutic potential for CX has remained a challenge, for generating undesired toxic side effects to the bladder. Crocetin, a natural carotenoid has been employed in the present studies to ameliorate the bladder toxicity of CX. Interestingly, crocetin at a dose of 50 mg/kg modulated the release of chloroacteldehyde, a urotoxic metabolite of CX in the urine of mice given combined treatment. Crocetin at the same dose significantly elevated Glutathione-S-Transferase enzyme activity both in the bladder and the liver of mice treated with CX. The exact mechanism of the protective effect of crocetin is not known, presumable it may act as an antioxidant, trapping and scavenging free radicals during the detoxification process. In Sarcoma-180 tumor bearing mice, crocetin has the ability to protect against CX induced bladder toxicity without altering its antitumor activity. Our studies are important to identify antioxidant rescue agents to overcome dose-limiting toxicity of CX.
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PMID:Protective effects of crocetin on the bladder toxicity induced by cyclophosphamide. 780 75

Glutathione (GSH) contributes to the detoxification of anticancer drugs through the operation of specific glutathione S-transferases (GST) and innate, or acquired, overexpression of this enzyme family has been frequently observed in tumor cell lines. In the GMA32 line of Chinese hamster fibroblasts, we showed that GSH starvation produced by exposing cells to buthionine sulfoximine (BSO) increased the toxicity of chlorambucil and melphalan, but not that of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), cisplatine and doxorubicin. This indicates that efficient mechanisms of detoxification using GSH operate for chlorambucil and melphalan, but not for the other drugs in these cells. We then showed that GSH depletion could be selectively and transiently induced in the mu GST overexpressing cell line derived from GMA32, HC474, by exposing cells to substrates specific to the overexpressed isozyme. Exposing cells to such a substrate, trans-stilbene oxide, does not alter the sensibility of GMA32 cells to melphalan and chlorambucil, but increases that of HC474 cells to these drugs, to an extent comparable to that obtained with BSO. This observation highlights the possibility of exploiting GST overexpression, a frequent feature of tumor cells, to selectively sensitize these undesirable cells to anticancer drugs.
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PMID:A glutathione depletion selectively imposed on mu glutathione S-transferase overproducing cells increases nitrogen mustard toxicity. 785 20

Glutathione-S-transferase (GST) in one of several factors that are proposed to affect tumor sensitivity to anticancer drugs, including cisplatin (CDDP). Attempts are made herein to evaluate the significance of the enzymes in resistance to CDDP in clinical samples of gastric cancer. A total of 22 gastric cancer specimens, 16 of which were obtained with matching normal mucosae, underwent immunoblotting with polyclonal antibodies against GST-alpha and GST-pi. At the same time, the chemosensitivity of 15 gastric cancer specimens to CDDP was evaluated by the succinic dehydrogenase inhibition (SDI) test. The expression of GST-pi was detected in all the specimens, and its content in the neoplasms exhibited a significant positive correlation with that in the matched normal mucosae. The expression of GST-alpha was detected in 18 of 22 cancer specimens (82%), but its content in the neoplasms did not correlate with that in the matched mucosae. A comparison of the drug-sensitivity findings with the results of immunoblotting revealed a weak but interesting correlation between the protein levels of GST-alpha and CDDP resistance. The cellular content of GST-alpha correlated weakly with CDDP resistance in gastric cancer, and its quantification could contribute to prediction of the clinical effects of CDDP in patients with gastric cancer.
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PMID:Expression of glutathione-S-transferases alpha and pi in gastric cancer: a correlation with cisplatin resistance. 800 52

Glutathione (GSH) concentrations in human epidermoid carcinoma tissues were measured by high performance liquid chromatography. The mean glutathione content of 26 epidermoid carcinoma intratumor tissue specimens was 24.36 nmol/mg protein, which was significantly higher than that in adjacent non-tumor tissue parts (3.04 nmol/mg protein). The mean concentration found in normal oral mucosa was 4.80 nmol/mg protein. Tissue GSH levels were not correlated with the age of the patients or tumor size. Additionally, cellular GSH levels in nine different cell lines were found to spread over a wide range from 0.97 to 50.97 nmol/mg protein. Elevated GSH levels in cancer tissues were probably due to their abnormal proliferative activities. These results indicate that the glutathione level of oral tissues may be a useful marker for oral cancer, which is in agreement with findings from lung squamous cell carcinoma, cervical squamous cell carcinoma and other squamous cell carcinomas.
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PMID:Glutathione concentration in oral cancer tissues. 801 28

We have measured glutathione content in small tissue samples derived from biopsies of primary and metastatic human colon tumors and from colon cancer cell lines in tissue culture and xenografts in athymic mice. Measurements were performed using an enzymatic cycling assay designed to quantitate extremely low levels of glutathione (GSH) (down to 10(-14) mol) from perchlorate extracts of tissue samples weighing less than 1 mg wet weight. Glutathione was stable in these acid extracts for at least 6 months when stored at -80 degrees C. A survey of normal tissues in mice, rats, and some human tissues showed considerable variation in GSH content of different tissues but generally similar levels were identifiable for the same tissues from different species. The highest GSH level was 56.9 nmol/mg protein in rat liver and the lowest was 1.8 nmol/mg protein in rat skeletal muscle. High GSH levels were also determined in mouse and human liver, while low GSH levels were detected in mouse muscle. Human colon cancer cell lines showed slightly higher GSH levels than did colon cancer tumor samples obtained from biopsies. These studies revealed a marked inter-individual difference in tumor GSH content, as well as a difference in GSH content between tumor deposits at different metastatic sites in the same individual. These results indicate the importance of direct tumor measurements of GSH content in clinical trials designed to modulate tumor glutathione content to try to increase sensitivity to chemotherapy or radiation therapy. Buthionine sulfoximine, an inhibitor of gamma-glutamyl cysteine synthetase, was shown to produce almost complete depletion of GSH in four different human colon cancer cell lines in 24 h. Buthionine sulfoximine was also shown to be capable of producing drastic depletion of GSH in human colon cancer grown as xenografts in athymic animals.
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PMID:Sensitive enzymatic cycling assay for glutathione: measurements of glutathione content and its modulation by buthionine sulfoximine in vivo and in vitro in human colon cancer. 803 40

Pouches of male Syrian Golden hamsters were painted with 1% 7,12-dimethylbenz[a]anthracene (DMBA) three times for one week. One week after DMBA treatment, hamsters were fed an ethanolic diet and continued on this diet until they were killed 22 and 35 weeks after the start of the experiment. Phospholipids, cholesterol, indexes of lipid peroxidation (malondialdehyde, diene and triene conjugates, lipid fluorescence), and the antioxidants glutathione and vitamin E were determined in the buccal mucosa, as was the incidence of tumors. At 22 weeks, the relative proportion of cholesterol to phospholipids in ethanol-consuming hamsters was significantly increased. At 35 weeks, most of the treatments showed a return of cholesterol vs. phospholipids toward that of untreated mucosa at 22 weeks. Ethanol consumption also increased the indexes of lipid peroxidation at 22 weeks; the largest increases occurred when ethanol use was combined with DMBA treatment. However, at 35 weeks such increases in lipid peroxidation had either returned to intermediate levels or were not different from the untreated controls at 22 weeks. Glutathione decreased in pouches of hamsters fed ethanol diets at 22 weeks, but at 35 weeks there was no appreciable difference. However, vitamin E increased significantly with ethanol consumption at 22 weeks, which increased further when combined with DMBA treatment, but at 35 weeks these values were intermediate. No tumors were seen at 22 weeks. At 35 weeks, DMBA-treated ethanol-fed hamsters had a significantly higher incidence of tumors, more multiple tumors per hamster with tumors, and more of the larger tumors than DMBA-treated control-fed hamsters. The results suggest that an increase in lipid peroxidation occurs with ethanol-related tumor promotion processes, but this lipid peroxidation declines when tumors appear to be preceded by increases in cholesterol relative to phospholipids and increases in vitamin E.
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PMID:Ethanol-mediated promotion of oral carcinogenesis in hamsters: association with lipid peroxidation. 810 78

Glutathione (GSH) and glutathione S-transferases (GSTs) play an important role in the protection of cells against toxic effects of many electrophilic drugs and chemicals. Modulation of cellular GSH and/or GST activity levels provides a potentially useful approach to sensitizing tumor cells to electrophilic anti-cancer drugs. In this study, we describe the interactions of four representative alkylating agents (AAs), melphalan, 4-hydroperoxy-cyclophosphamide (4HC), an an activated form of cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and cisplatin, with GSH and GST in the human breast cancer cell line MCF-7. Depletion of cellular GSH pools by approximately 80% by treatment of the cells with the GSH synthesis inhibitor buthionine sulfoximine (BSO) sensitized the tumor cells to each AA to a different extent, with dose-modifying factors of 2.39, 2.21, 1.64, and 1.27 observed for melphalan, 4HC, cisplatin, and BCNU, respectively. Treatment of the cells with the GST inhibitor ethacrynic acid (EA) failed to show any significant effects on the cytotoxicity of these AAs. However, EA did potentiate the cytotoxicity of melphalan when given in combination with BSO, an effect that may be due to a more complete depletion of cellular GSH levels by the combined modulator treatment. Following a 1-hr exposure to cytotoxic-equivalent concentrations of these AAs, GSH levels decreased substantially in the case of 4HC and BCNU, but increased by 30-50% in the case of cisplatin and melphalan. BSO pretreatment largely blocked this effect of cisplatin and melphalan on cellular GSH, while it further enhanced the GSH-depleting activity of both 4HC and BCNU. On the basis of these results, it is concluded that (a) GSH affects the cytotoxicity of different AAs to different extents, (b) basal GST expression in MCF-7 cells does not play a major role in AA metabolism, (c) EA can potentiate the enhancing effect of BSO on melphalan cytotoxicity in MCF-7 cells, and (d) depletion of cellular GSH by pretreatment with BCNU or cyclophosphamide may correspond to a useful strategy for enhancing the anti-tumor activity of other AAs given in a sequential combination.
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PMID:Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells. 814 7

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

Glutathione and glutathione-related enzymes have been implicated in sensitivity of tumors to chemotherapeutic drugs. In the present study, glutathione and the activity of its related enzymes were quantitated in 4 renal cell carcinoma cell lines and 4 bladder carcinoma cell lines. The expression of glutathione-s-transferase pi and alpha in each cell line was analyzed by immunoblot analysis. The relationships between glutathione levels, glutathione peroxidase activity and glutathione-s-transferase activity and tumor sensitivity to cisplatinum, doxorubicin and vinblastine were determined by linear regression analysis. Glutathione levels were positively related to cisplatinum resistance in both renal cell carcinoma and bladder carcinoma cell lines and to doxorubicin resistance in bladder carcinoma cell lines. A positive correlation between glutathione peroxidase activity and doxorubicin resistance was identified in renal cell carcinoma cell lines, but no correlation was noted in bladder carcinoma cell lines. No significant correlation was apparent between glutathione-s-transferase activity and sensitivity to any of the drugs tested in this study. To further clarify the relationship between glutathione levels and the cytotoxicity of the drugs, we evaluated the effect of glutathione depletion by L-buthionine sulfoximine on the cytotoxicity of the drugs in bladder carcinoma cell lines. Glutathione depletion enhanced cisplatinum cytotoxicity 1.3- to 1.7-fold and doxorubicin cytotoxicity by 1.45- to 11.2-fold. Glutathione depletion did not change vinblastine cytotoxicity. The present study demonstrates that glutathione and its related enzymes affect sensitivity to cisplatinum or doxorubicin. The drug resistance mechanism elicited by glutathione and its related enzymes in these tumors needs further elucidation so that chemotherapeutic regimens may be modified.
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PMID:Effect of glutathione and its related enzymes on chemosensitivity of renal cell carcinoma and bladder carcinoma cell lines. 825 25


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