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)

Several halogenated alkenes are nephrotoxic; some others induce renal tubular adenocarcinomas in rodents after lifelong administration. A bioactivation mechanism accounting for the organ-selective tumor induction has been elucidated: conjugation of the parent compounds with glutathione (GSH), catalyzed by hepatic GSH S-transferases, results in the formation of haloalkyl and halovinyl glutathione S-conjugates. Formation of S-conjugates (identified by NMR and mass spectrometry) could be demonstrated with trichloroethene, tetrachloroethene, hexachlorobutadiene, perfluoropropene, trichlorotrifluoropropene, and dichloroacetylene in incubations with rat liver microsomes and in the isolated perfused rat liver. The GSH conjugates formed are eliminated from the rat liver with the bile and may be translocated to the kidney, intact or after metabolism to the corresponding cysteine S-conjugates that are metabolized in the kidney by renal tubular cysteine conjugate beta-lyase (beta-lyase) to reactive intermediates, most likely thioacylchlorides and thioketenes. Interaction of these potent electrophiles with DNA [demonstrated for intermediates formed from S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine] causes mutagenicity in bacteria, genotoxicity in cultured renal cells, and cytotoxicity in kidney cells. As an alternative to beta-lyase-catalyzed cleavage, the cysteine S-conjugates may be acetylated to the corresponding mercapturic acids, which have been identified in urine. The ability of the kidney to concentrate GSH and cysteine S-conjugates and the intensive metabolism of GSH S-conjugates to cysteine S-conjugates in this organ are evidently responsible for the organotropic carcinogenicity.
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PMID:A mechanism of haloalkene-induced renal carcinogenesis. 227 3

Though various chemotherapy protocols lead to considerable response rates in squamous cell head and neck cancer (SCHNC), the overgrowth of a tumor cell phenotype which no longer responds to clinically achievable drug concentrations regularly impairs definite tumor control. In order to investigate mechanisms of drug resistance towards one of the most active agents in SCHNC we established four Cisplatin (CDDP)-resistant sublines (DDP1-DDP4) of the recloned human SCHNC cell line HLac 79. The 50% inhibitory drug concentration (IC50) of CDDP as determined by the colorimetric MTT-assay was increased by the factors 2.7 (DDP1), 3.3 (DDP2), 5.1 (DDP3), and 6.4 (DDP4) in the respective sublines. Three subpopulations contained significantly elevated glutathione (GSH) levels by the factors 1.4 (DDP3), 1.7 (DDP2), and 2.4 (DDP4) compared to the maternal line (50.2 nM/mg protein). DDP4 showed increased activity of gamma-glutamyl-transpeptidase (1.83 vs. 1.21 mU/mg protein), and DDP2 and DDP4 showed increased activity of GSH-S-transferase (35.6 and 51.9 vs. 25.1 mU/mg protein). Concerning both GSH-peroxidase and GSH-reductase no significant differences between the HLac 79 subpopulations were observed. Intracellular CDDP accumulation determined by neutron activation analysis revealed reduced drug uptake in DDP3 and DDP4 (60% and 76% of control value).
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PMID:Establishment and characterization of cisplatin-resistant sublines of the human squamous carcinoma cell line HLac 79. 228 22

By treating a human tumor cell line with various concentrations of diamide, we explored the relationship between extent and duration of protein and nonprotein thiol oxidation, initiation of DNA double-strand break rejoining after X-rays, and the degree of radiosensitization. We also examined the relationship between protein thiol status and the non-protein thiol, glutathione (GSH). A549 cells were irradiated and incubated postirradiation with 0, 100, 300 or 500 microM diamide for 1 h. The dose of radiation required to give 10% survival decreased from 4.8 Gy to 3.2 Gy with 300 microM and to 2.7 Gy with 500 microM diamide (enhancement ratios of 1.5 and 1.8, respectively) but was not significantly affected by 100 microM diamide. The time of initiation of double-stranded DNA rejoining after X-irradiation (DNA repair) was delayed by 300 and 500 microM diamide. Furthermore, DNA rejoining began only after total cellular protein thiol content recovered to 55% of pretreatment levels for both concentrations. Intracellular GSH/GSSG ratios decreased immediately after diamide addition to less than 1. Large decreases in GSH/GSSG ratio preceded significant loss of protein thiols, but protein-glutathione mixed disulfides accounted for a minor percentage of the total protein thiol oxidized (up to 20%). We believe that diamide-induced protein thiol loss, and not GSH oxidation, is related to the cessation of DNA strand rejoining after X-irradiation, thereby affecting survival.
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PMID:Diamide induced shift in protein and glutathione thiol: disulfide status delays DNA rejoining after X-irradiation of human cancer cells. 229 69

Recent studies have suggested that differences in the initial low-dose region of the radiation survival curves for human tumor cells might explain the differences in clinical response of tumors to fractionated radiation treatment. In this study, which is described in two companion papers, we investigated this hypothesis directly using animal model systems. In the present paper we determined in vitro radiation survival curves for eight murine tumor cell lines of varying histopathological type and: (a) measured survival at the 2 Gy and 8 Gy dose levels, (b) fitted parameters to the linear quadratic and two component multi-target equation models of cellular survival and (c) calculated mean inactivation doses. We found that the choice of the data fitting procedure affected the absolute value, relative ranking, and power to discriminate between the cell lines of these calculated parameters. A detailed statistical study indicated that the measured surviving fraction at 2 Gy (SF2) was the best discriminant of intrinsic radiosensitivity between the eight tumor cell lines. When these same cell lines were assayed for intracellular glutathione (GSH) levels, no correlation was found between levels of GSH and the SF2 value. Determining the SF2 value may be the method of choice to describe the low-dose region of the radiation survival curve, as it precludes the necessity of choosing a model to fit the survival data, it has excellent discriminatory powers, and it represents the survival in the radiotherapeutically relevant region of the in vitro radiation survival curve. Furthermore, as demonstrated in the companion paper, it correlates with cell survival in the tumors following 10 fractions of 2 Gy given in vivo.
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PMID:Comparison between in vitro radiosensitivity and in vivo radioresponse of murine tumor cell lines. I: Parameters of in vitro radiosensitivity and endogenous cellular glutathione levels. 229 17

The success of antineoplastic chemotherapy in head and neck carcinoma is limited by the insufficient primary chemosensitivity of the tumor and/or the decrease of drug efficacy in the course of treatment. As regards cisplatin (CDDP) this phenomenon of chemoresistance may be closely associated with glutathione (GSH) metabolism since GSH is responsible for the detoxication of active CDDP hydrolysates. In the human squamous carcinoma cell line HLac 79, selective inhibition of GSH synthesis by buthionine sulfoximine (BSO) led to enhanced CDDP chemosensitivity both in vitro and in vivo. Using the colony-forming assay GSH depletion of HLac 79 tumor cells of more than 90% (Table 1) resulted in a dose modifying factor of 2 (Table 2). Combined treatment of HLac 79 tumor-bearing nude mice with BSO and CDDP brought about significant increase in mean survival time (p less than 0.001) as compared to the CDDP-treated group. The possible role of BSO as chemosensitizer is discussed.
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PMID:[Increasing chemosensitivity to cisplatin by glutathione depletion with buthionine sulfoximine. In vitro and in vivo studies with a human squamous cell cancer line]. 231 Apr 56

Many antineoplastic agents alter the reduced glutathione (GSH) status of liver and tumor tissue by inhibiting cellular GSH-linked enzymes. Thus, intracellular GSH plays an important role in a wide variety of antineoplastic interventions regarding therapeutic efficacy and toxicity. Mean GSH values were 0.791 +/- 0.072 mg/m wet weight (ww) and 0.719 +/- 0.047 mg/g ww in gastric cancer tissue and nontumorous glandular mucosa, respectively. Whereas, the average GSH level of normal gastric mucosa was 1.709 +/- 0.135 mg/g, the mean GSH level of normal liver biopsies was 2.378 +/- 0.260 mg/g. The GSH values of normal liver tissue were higher than the hepatocellular GSH concentrations of patients with gastric adenocarcinoma and of another group of tumor-bearing patients who had received chemotherapy preoperatively. These results suggest that the GSH levels of tumor and liver may influence the efficacy and/or toxicity of chemotherapeutic agents.
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PMID:Liver glutathione contents in patients with gastric adenocarcinomas. 232 Dec 74

Roles of oxygen free radicals in recombinant human TNF- and human lymphotoxin (LT)-mediated cytotoxicity have been examined. Nimustine (ACNU), which inhibits glutathione reductase, and buthionine sulphoximine (BSO), an inhibitor of glutathione (GSH) synthesis, were used to modify the steady-state level of intracellular H2O2. TNF-mediated cytotoxicity was augmented when ACNU was added simultaneously to target L cells or Meth A tumor cells. Similar augmented effect was observed when TNF or LT was added to ACNU-treated target cells. However, the addition of GSH nullified the augmentation of TNF-mediated cytotoxicity to ACNU-treated Meth A tumor cells. Meth A tumor cells were pretreated with BSO for 24 hr, and thereafter TNF or LT was added in the presence or the absence of BSO. The cytotoxic effect of TNF and LT was augmented by the treatment of the cell with BSO or simultaneous addition of BSO. High degree of the augmentation was obtained when the pretreatment with BSO and further addition of BSO were combined. These results suggest that oxygen free radicals are closely involved in TNF- and LT-mediated cytotoxicity and the modulation of intracellular GSH level alters the degree of the cytotoxicity of these cytotoxins.
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PMID:[Augmentation of TNF- and lymphotoxin-mediated cytotoxic effect in the combined use of ACNU and involvement of oxygen free radicals]. 232 76

Treatment of confluent cultures of human diploid fibroblasts with 12-O-tetradecanoylphorbol-13-acetate (TPA) (10(-7) M) resulted in a 70% reduction of the glutathione (GSH) content, compared with untreated controls. The effect, which was dose-dependent, was observed 8 h after the beginning of the treatment could be followed for up to 72 h. On the other hand, GSH reduction was specific for confluent cultures, as the level of glutathione remained unchanged by TPA treatment of sparse cultures. The addition of immobilized plasma membrane proteins to sparsely seeded cells has been shown previously to induce cellular reactions which are characteristic for confluent cultures. It was shown that TPA treatment of sparse cultures grown in the presence of immobilized plasma membrane proteins also resulted in a 70% reduction of glutathione content. These data agree with the postulated involvement of redox reactions in tumor promotion, and point to a central role of cell-cell contacts in the regulation of biochemical events which are critical in tumorigenesis.
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PMID:Reduction of glutathione content by 12-O-tetradecanoylphorbol-13-acetate in confluent, but not in sparse cultures of human diploid fibroblasts. 232 9

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

Glutathione-S-transferase (GST) activity and glutathione (GSH) content have been studied in human urinary bladder (UB) specimens obtained from healthy controls (HC) (n = 8) and from patients with superficial transitional cell carcinoma (TCC) (n = 9), either in TCC and in adjacent normal (ANE) tissues of the same patient. The GST activity was significantly higher in TCC in comparison with ANE (ten fold) and with HC (five fold). This activity was also significantly higher in HC than in ANE (two fold). The Km values obtained in the whole population (1.26 +/- 0.3 X 10(-3) mol/l) suggest that a unique form of isoenzyme is present in the UB epithelium and that it is the same acidic form "rho" described in erythrocytes. The GSH content was significantly higher in TCC than in ANE (2.5 fold) and also that in HC (three fold). A good correlation between GST activity and GSH content was observed in HC but not in TCC or ANE. These results demonstrate the relation between the activity of the GST system and the development of the TCC as well as its role in the cellular resistance to chemotherapy. A possible decrease of the GST activity before the development of the tumor is also discussed.
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PMID:Glutathione-S-transferase activity in human superficial transitional cell carcinoma of the bladder. Comparison with healthy controls. 237 71


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