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)

Cellular glutathione (GSH) levels were measured from 27 human lung tumor biopsies, enzymatically disaggregated, and compared with cells isolated from normal lung of the same patients. GSH levels from normal lung were similar among patients with a mean value of 11.20 +/- 0.58 (SEM) nmol GSH/mg protein (24 patients) with a range from 6.1 to 17.5 nmol GSH/mg protein. GSH levels varied considerably within and across histological tumor types with the following values: adenocarcinomas, 8.83 +/- 0.96 nmol/mg protein (8 patients); large cell carcinomas, 8.25 +/- 2.51 nmol/mg protein (3 patients); and squamous cell carcinomas, 23.25 +/- 5.99 nmol/mg protein (8 patients). The cyclic GSH reductase assay gave only average GSH values and could not distinguish possible GSH variation among subpopulations of cells isolated. Cell volume measurements and microscopic evaluation of cells isolated from both tumors and normal lung revealed heterogeneity with respect to cell types present. To determine the extent of thiol variation among tumor cell subpopulations, tumor cell suspensions were stained with the thiol-specific stain, monochlorobimane (MCB). The accuracy of MCB staining was tested by flow cytometric analysis of 12 in vitro human tumor cell lines and 3 rodent cell lines. A linear relationship was found between the bimane cellular fluorescence and the cyclic GSH reductase assay for cell lines having less than 80 nmol GSH/mg protein (R2 = 0.82). Above 80 nmol GSH/mg protein the rate of change of the bimane fluorescence intensity with respect to increasing GSH concentrations was much reduced. However, by labeling cells with MCB it was possible to distinguish between cell lines with low versus high GSH content. MCB staining of tumor samples revealed multiple populations of cells with respect to thiol levels. In particular, 2 of 8 squamous cell carcinomas had a proportion of cells with elevated fluorescence intensities (from 10 to 35% of the population) suggesting the presence of cells with greatly elevated thiol levels. These findings underscore the complexity of quantitating intracellular GSH levels from tumor biopsies. The combined use of MCB with flow cytometry and conventional GSH assays may help to delineate subpopulations of cells within tumors with different thiol levels.
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PMID:Cellular glutathione and thiol measurements from surgically resected human lung tumor and normal lung tissue. 186 49

Technetium-d, HMPAO SPECT was performed in 70 patients suffering from intracerebral tumors of various histologic types (glioma n = 30, meningioma n = 19, metastases n = 10, angioma n = 3, neuroma n = 2, lymphoma n = 2, neurocytoma n = 1, epidermoid n = 1, gliosis n = 1, cholesteatoma n = 1). Tumor classification was histologically verified in all subjects except in two cases with inoperable angiomas. SPECT was performed under resting state conditions with a dual-head rotating camera (SIEMENS ZLC 37) following intravenous injection of 18-25 mCi 99mTc-d, 1-HMPAO. Regional tracer deposit was expressed in terms of a cerebellar index (CBI). Significantly higher regional HMPAO uptake was found in meningiomas when compared with gliomas of different malignancy (ANOVA p less than 0.05). Within gliomas, regional uptake increased with malignancy (n.s.). In 23 patients, a total of 32 tumor specimens were obtained for histochemical analysis of glutathione (GSH) content using high-pressure liquid chromatography. A significant correlation (least square method, p less than 0.001) between CBIs and GSH values was found, supporting the hypothesis that GSH is the predominant factor for the conversion of the lipophilic complex to hydrophilic derivates.
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PMID:Technetium-99m-d,1-hexamethylpropyleneamine oxime (HMPAO) uptake and glutathione content in brain tumors. 188 May 68

Glucose oxidase (GO) catalyzes the conversion of beta-D-glucose and molecular oxygen to D-glucono-delta-lactone and H2O2. H2O2 produced by GO was effective in preventing tumor growth in mice bearing not only ascites tumor but also solid tumor. The effect of GO was enhanced by the combined administration of catalase inhibitors such as 3-aminotriazole, hydroxylamine and sodium azide or the GSH synthesis inhibitor buthionine-(S,R)-sulfoximine in vivo. The cytolytic activity of GO against T-24 cultured cells in vitro was also enhanced by addition of these inhibitors together with GO. In the peritoneal cavity of mice the antitumor effect of GO seemed to be dependent on the amount of oxygen released from oxygenated fluorocarbon-43 (FC-O2), an oxygen-supplying substance. Furthermore, the combined administration of H2O2-decomposing enzyme inhibitors and FC-O2 synergistically enhanced the antitumor effect of GO. These results suggest that GO is suitable for antitumor chemotherapy and that the use of inhibitors of H2O2-decomposing enzymes and FC-O2 potentiated the GO therapy.
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PMID:Enhancement of the antitumor effect of glucose oxidase by combined administration of hydrogen peroxide decomposition inhibitors together with an oxygenated fluorocarbon. 191 30

1,2-Dibromo-3-chloropropane is a potent renal and testicular toxicant and has been shown to induce tumor formation in laboratory animals. The toxic effects of the compound are thought to be a result of a bioactivation step in which a glutathione conjugate is formed and subsequently reacts with cellular DNA. The L-glutathione conjugate of 1,2-dibromo-3-chloropropane was chemically synthesized and used to alkylate DNA: following incubations of the conjugate with calf thymus DNA and neutral thermal hydrolysis (to release N7-guanyl adducts) four major fluorescent products were observed. Three of these were isolated and characterized, the structures being determined as S-[bis(N7-guanylmethyl)methyl]glutathione and the two diastereomers of S-[1-(hydroxymethyl)-2-(N7-guanyl)ethyl]glutathione. The fourth fluorescent product was unstable and formed in low yield and thus could not be characterized. The formation of these N7-guanyl adducts can be explained by a mechanism that includes the formation of two consecutive episulfonium ion intermediates followed by nucleophilic attack at the unsubstituted methylene carbon. These adducts bear structural and mechanistic similarities to the major adduct derived from 1,2-dibromoethane, S-[2-(N7-guanyl)ethyl]glutathione. The same adducts were also formed when DBCP was incubated with rat liver cytosol, GSH, and DNA. In vivo experiments with DBCP yielded very low levels of the N7-guanyl adducts formed in rat liver compared to the levels seen after treatments with 1,2-dibromoethane. The bis-guanyl adduct represents a cross-linked structure that may be important in the toxicity of this compound. The conjugate was not found to be mutagenic to Salmonella typhimurium TA100 but rather showed a toxic effect toward the bacteria.
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PMID:Isolation and characterization of N7-guanyl adducts derived from 1,2-dibromo-3-chloropropane. 191 32

Quinones are probably found in all respiring animal and plant cells. They are widely used as anticancer, antibacterial or antimalarial drugs and as fungicides. Toxicity can arise as a result of their use as well as by the metabolism of other drugs and various environmental toxins or dietary constituents. In rapidly dividing cells such as tumor cells, cytotoxicity has been attributed to DNA modification. However the molecular basis for the initiation of quinone cytotoxicity in resting or non-dividing cells has been attributed to the alkylation of essential protein thiol or amine groups and/or the oxidation of essential protein thiols by activated oxygen species and/or GSSG. Oxidative stress arises when the quinone is reduced by reductases to a semiquinone radical which reduces oxygen to superoxide radicals and reforms the quinone. This futile redox cycling and oxygen activation forms cytotoxic levels of hydrogen peroxide and GSSG is retained by the cell and causes cytotoxic mixed protein disulfide formation. Most quinones form GSH conjugates which also undergo futile redox cycling and oxygen activation. Prior depletion of cell GSH markedly increases the cell's susceptibility to alkylating quinones but can protect the cell against certain redox cycling quinones. Cytotoxicity induced by hydroquinones in isolated hepatocytes can be attributed to quinones formed by autoxidation. The higher redox potential benzoquinones and naphthoquinones are the most cytotoxic presumably because of their higher electrophilicty and thiol reactivity and/or because the quinones or GSH conjugates are more readily reduced to semiquinones which activate oxygen.
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PMID:Molecular mechanisms of quinone cytotoxicity. 191 77

The glutathione transferases comprise a family of isoenzymes, one or more of which are involved in the conjugation of alkylating agents to glutathione (GSH). Increased GSH transferase activity has been shown to underlie acquired resistance to several alkylating agents. Ethacrynic acid inhibits the isoenzymes of GSH transferase with 50% inhibitory concentration values ranging from 0.3 to 6.0 microM and has been shown to restore sensitivity to alkylating agents in drug-resistant animal tumor models. We entered 27 previously treated patients with advanced cancer on a study of ethacrynic acid (25 to 75 mg/m2 p.o. every 6 h for 3 doses) and thiotepa (30 to 55 mg/m2 i.v. 1 h after the second dose of ethacrynic acid). The major toxicity of ethacrynic acid was diuresis, which was observed at every dose level; in addition, severe metabolic abnormalities occurred at 75 mg/m2. At 50 mg/m2, the diuretic effects were manageable. Myelosuppression was the most important effect of the combination. Two of seven courses of ethacrynic acid, 50 mg/m2, and thiotepa, 55 mg/m2, were associated with grade 3 or 4 neutropenia and/or thrombocytopenia. Nausea/vomiting greater than or equal to grade 2 was observed in 16% of courses. GSH transferase activity was assayed spectrophotometrically in the peripheral mononuclear cells of all patients. At each dose level, activity decreased following ethacrynic acid administration, with recovery by 6 h. Administration of ethacrynic acid, 50 mg/m2, resulted in a mean nadir of transferase activity of 37% of control. The pharmacokinetics of thiotepa and its principal metabolite TEPA were studied in 23 patients. The plasma disappearance of thiotepa fit a two-compartment open model with a terminal half-life of approximately 2 h. Plasma TEPA levels peaked at a mean of 2.16 h following thiotepa administration. The harmonic mean terminal half-life of TEPA was 10.4 h, and the TEPA area under the curve (AUC) did not increase with increasing thiotepa dose. The AUC of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA was lower than that previously observed. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA. The severity of the platelet toxicity was correlated with the AUC of thiotepa, but not with that of TEPA. This combination of thiotepa and ethacrynic acid will be tested further in Phase II trials.
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PMID:Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. 193 69

In a previous report we have characterized cisplatin (CDDP)-resistant sublines (HLac 79-DDP1 to DDP4) of the recloned squamous cell head and neck cancer (SCHNC) line HLac 79-ML revealing significant alterations of glutathione (GSH) metabolism and drug accumulation. In order to overcome CDDP-resistance in HLac 79 cells we now investigated the effect of buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, verapamil (VRP), a calcium channel blocker that has been found to modulate resistance towards a broad spectrum of antineoplastic drugs, cyclosporin A (CSA), an immunosuppressive agent probably affecting drug pharmacokinetics, and aphidicolin (APC), a fungal metabolite interfering with DNA repair through inhibition of DNA polymerase alpha, on HLac 79 CDDP-sensitivity. Using the colorimetric MTT assay, GSH depletion with BSO led to a significant decrease of the 50% inhibitory drug concentration (IC50) in all HLac 79 sublines by dose modifying factors (IC50 CDDP/IC50 BSO + CDDP) ranging from 1.8 to 3.3. VRP, CSA or APC were not effective to overcome CDDP resistance in HLac 79 cells. The potential of BSO to modulate CDDP resistance in vitro was tested in vivo in HLac 79 tumor bearing NMRI nu-nu mice subsequently. Oral administration of BSO 7 days prior and during (days -7 to 8) CDDP treatment (3 mg/kg bw i.p. days 0, 4, 8) produced a significant prolongation of mean survival time mean as compared to chemotherapy alone. This held true for both the maternal line ML in terms of chemosensitization (CDDP: mean = 40.2 +/- 15.9 days vs. CDDP + BSO: mean = 80.3 +/- 30.4 days, p less than 0.001) and the CDDP resistant subline DDP4 in terms of partially overcoming secondary drug resistance (CDDP: mean = 56.5 +/- 13.6 days vs. CDDP + BSO: mean = 72.5 +/- 15.8 days, p less than 0.001). Enhanced toxicity of combined BSO and CDDP treatment manifested by transient 10% reduction of animal mean body weight.
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PMID:Circumvention of drug resistance in cisplatin-resistant sublines of the human squamous carcinoma cell line HLac 79 in vitro and in vivo. 195 May 44

The effect of endotoxin on colon tumors was studied in male Sprague-Dawley rats. Colon tumors were induced in weanling rats by the administration of 20 weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH). When colon tumors were detected by colonoscopy in 80% of the rats around week 24 after DMH injection, the animals were divided randomly into two groups. One group served as the control. The other group received six endotoxin (Escherichia coli) treatments every fifth day. The first dose was 50 micrograms/100 g (intraperitoneally); the remaining doses were 100 micrograms/100 g (subcutaneously). Rats were killed 2 weeks after the last endotoxin injection. Endotoxin treatments resulted in larger colon tumors. The median tumor size was 71 mm2 for endotoxin-treated and 31 mm2 for untreated rats (P less than 0.02). Endotoxin treatments also resulted in a significantly higher incidence (P less than 0.05) of ulcer development in the small intestine, that is 47% in the endotoxin-treated versus 23% in the untreated rats. After a single subcutaneous injection of endotoxin (100 micrograms/100 g), the colon mucosal reduced glutathione (GSH) level was raised by 21% at 16 hours, reached a peak on day 2, then decreased to baseline by day 4. The increased GSH level in the colon mucosa was maintained up to the third endotoxin injection. By the fifth injection, no increase in the GSH level was observed. These results suggest that the growth of colon tumors in rats induced by DMH could be enhanced by endotoxin treatments. The enhanced tumor growth may be due to an increase in the colon GSH level and/or other mediators released by macrophages as a result of endotoxin treatments.
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PMID:The effect of endotoxin on 1,2-dimethylhydrazine-induced colonic tumors in rats. 196 25

Resistance of tumor cells to chemotherapeutic drugs may be due to several mechanisms within a single cell line. Resistance to doxorubicin in the human multidrug resistant breast cancer cell line, MCF-7 AdrR, has been attributed to increased glutathione (GSH) S-transferase and GSH peroxidase activity, as well as to increased expression of the mdr1 gene product, P-glycoprotein. We studied the potentiation of doxorubicin activity in these cells by buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, and by verapamil and trans-flupenthixol, agents which interact with P-glycoprotein. Treatment with BSO enhanced the effect of doxorubicin by 1.5-fold, while verapamil or transflupenthixol caused a greater reversal of drug resistance. The combination of BSO with trans-flupenthixol produced no further potentiation of doxorubicin activity. However, the combination of BSO with verapamil and doxorubicin caused up to a 10-fold increment in antiproliferative effect. To explore the mechanism by which BSO interacted with this drug combination, we determined whether or not BSO might potentiate the effects of verapamil. These studies demonstrated that the effects of BSO were predominantly due to an increase in verapamil toxicity rather than to doxorubicin toxicity. In addition, when mice received concentrations of BSO in their drinking water sufficient to deplete GSH and were treated with verapamil, the calcium channel blocker was lethal to 9 of 12 mice receiving BSO compared to 1 of 10 control animals receiving verapamil alone. These studies demonstrate that BSO does not markedly increase the pharmacological effect of doxorubicin against MCF-7 AdrR cells and suggest that alterations in GSH and related enzymes are not a major factor in drug resistance in this cell line. Furthermore, BSO can increase the toxicity of verapamil, a finding which may have important implications for clinical trials.
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PMID:Effect of buthionine sulfoximine on toxicity of verapamil and doxorubicin to multidrug resistant cells and to mice. 198 8

Glutathione transferases are enzymes implied in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We have investigated the effect of the glutathione transferase inhibitor by ethacrynic acid on the cytotoxicity of melphalan to a human melanoma cell line (RPMI 8322) with a high level of glutathione transferase activity. Using 1-chloro-2,4-dinitrobenzene as substrate, ethacrynic acid was shown to inhibit the activity of purified human glutathione transferases, with 50% inhibition values of 1, 10, and 15 microM for transferase mu (class mu), transferase epsilon (class alpha) and transferase pi (class pi), respectively, all of which occur in RPMI 8322 cells. Ethacrynic acid at a concentration of 20 microM, which by itself was noncytotoxic, increased the cytotoxicity of melphalan to RPMI 8322 human melanoma cells approximately 2-fold. The induction of DNA interstrand cross-links by 40 microM melphalan was increased 1.4-fold by 30 microM ethacrynic acid. These results indicate that a potentiation of the cytotoxic effect of bifunctional alkylating agents can be achieved by inhibition of glutathione transferase and that the enhanced cytotoxicity may be caused at least in part by increased formation of drug-DNA adducts.
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PMID:Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid. 198 11


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