Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione levels were measured in 30 human lung cancer lines. Lower levels were detected in cell lines derived from small cell lung cancer specimens compared to non-small cell lines (mean 42 vs. 130 nmol mg-1 protein, P = 0.005). However, no difference were detected between cell lines derived from previously untreated patients, compared to those derived from patients who had received chemotherapy. Non-small cell lines were found to have increased activity of 4 detoxification enzymes compared to small cell lines, although these differences did not reach statistical significance: glutathione transferase activity (69 vs. 36 units, P = 0.137), glutathione reductase (139 vs. 82 units, P = 0.05), gamma-glutamyl transpeptidase (9.39 vs. 3.03 units, P = 0.072) and superoxide dismutase (20 vs. 13.6 units, P = 0.137). As the cell lines exhibit a similar chemosensitivity pattern to that observed in clinical practice, these differences in glutathione and detoxification enzyme levels may prove to be important indicators of intrinsic drug resistance often seen in patients with non-small cell lung cancer.
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PMID:Glutathione and related enzyme activity in human lung cancer cell lines. 290 63

It has been established that the pyrogallol autoxidation method for the estimation of the activity of superoxide dismutase (SOD) (EC 1.15.1.1) is superior in precision and sensitivity to a superoxide-generating method (NADH/phenazine methosulfate linked to nitroblue tetrazolium reduction). Reference intervals were established in an urban population in the Far East for SOD activity in erythrocytes using the pyrogallol method, and for glutathione peroxidase (GSH-Px) (EC 1.11.1.9) activity in erythrocytes using a standard glutathione reductase-linked method. On this basis, erythrocyte SOD activities were significantly (P less than 0.05) depressed in cases of visceral cancer, acute myocardial infarct, congestive heart failure, respiratory failure, chronic renal failure, and diabetes mellitus, but within the reference interval in cases of lung cancer and asthma. Erythrocyte GSH-Px activity was significantly (P less than 0.05) depressed in cases of diabetes mellitus and chronic renal failure but elevated in respiratory failure and asthma. GSH-Px and SOD activities were well correlated in patients but not in the reference population.
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PMID:Superoxide dismutase and glutathione peroxidase activities in erythrocytes as indices of oxygen loading in disease: a survey of one hundred cases. 366

Human lung cancers of distinct histology exhibit different responses to radiation therapy in vivo. For examination of the basis of this phenomenon, the radiation survival curves and levels of relevant enzymes were determined in 16 lung cancer cell lines derived from tumors of different histology. These included lines from 5 adenocarcinomas, 7 small cell tumors, 3 variant small cell tumors, and 1 large cell tumor. These findings were compared to those obtained with the use of a normal skin fibroblast cell line. Whether cloned in liquid culture or soft agarose, cell lines had similar radiation survival curves. These curves were consistent with the apparent in vivo radiation responsiveness of the tumors. Although considerable heterogeneity in radiation survival curves was observed among the cell lines, cells from large cell lines and small variant lines had pronounced shoulders and extrapolation numbers (n) from 5.6 to 14. In contrast, cells from small cell lines and adenocarcinoma cell lines were more "sensitive" (-n values of 1-3.3). In these cell lines, levels of DNA polymerase beta, glutathione (GSH), GSH transferase, GSH reductase (NAD(P)H), gamma-glutamyltransferase did not correlate with radiation parameters of sensitivity. DNA polymerase beta and GSH levels were, however, higher than those in a line of normal skin fibroblasts. These cell lines may be useful in identifying the basis of the variable responsiveness of human lung cancer cells to ionizing radiation.
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PMID:Heterogeneity in the radiation survival curves and biochemical properties of human lung cancer cell lines. 614 44

Glutathione (GSH)-depletion by buthionine sulphoximine (BSO) altered both the aerobic and anaerobic radiation response of A549 human lung cancer cells grown in vitro. The oxygen enhancement ratio (o.e.r) was increased slightly from 3.0-3.3. The lack of an effect of GSH-depletion on o.e.r. reduction, provides a system whereby the mechanism of action of the thiol reactive reagent diethylmaleate (DEM) can be investigated. Pretreatment of cells with DEM, under non-toxic concentrations, removed 13 per cent of the intracellular NPSH and resulted in an o.e.r. of 2. When BSO followed by DEM was used, so that both GSH and NPSH were reduced to zero, an o.e.r. of 1.5 was obtained. Cells treated with 1 mM BSO for 24 hours contained 10 per cent NPSH and no GSH. When these cells were exposed to 0.5 or 1 mM DEM briefly, during irradiation, the o.e.r. was 2.4 and 1.7 respectively. In some cases altered o.e.r.s occurred in combination with increased aerobic responses. This was especially true for aerobic irradiations of BSO-treated cells in the presence or absence of DEM. However, the increased aerobic response was offset by a more dramatic increase in the hypoxic response. These results indicate (a) that GSH plays a significant role in aerobic radiation response but is not a principal factor in o.e.r.-reduction, and (b) that reduction of the o.e.r. by DEM is not due primarily to GSH-removal. The preferential radiosensitization of hypoxic cells by DEM may involve reactions of this compound with NPSH or protein SH, or may be related to the ability of DEM to mimic oxygen as a hypoxic cell radiosensitizer.
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PMID:Nonprotein thiols and the radiation response of A549 human lung carcinoma cells. 660 51

The ATP-dependent glutathione S-conjugate export pump (GS-X pump) has been suggested to play a role in the mechanism of cisplatin resistance. The purpose of this study was to determine the relationship between intracellular glutathione (GSH) levels and GS-X pump activity and whether GS-X pump overexpression results in cisplatin resistance. We transfected the human gamma-glutamylcysteine synthetase (gamma-GCS) gene into a human small-cell lung cancer cell line, SBC-3, producing SBC-3/GCS. The intracellular GSH content of SBC-3/GCS was twice that of the parental line, its GS-X pump activity was significantly enhanced and cellular cisplatin accumulation decreased. SBC-3/GCS showed higher resistance (relative resistance value of 7.4) to cisplatin than the parental line SBC-3. These data indicate that gamma-GCS gene overexpression induces cellular cisplatin resistance associated with increases in both the GSH content and GS-X pump activity, resulting in reduced cisplatin accumulation. In conclusion, GS-X pump expression is related to cellular GSH metabolism and involved in cisplatin resistance.
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PMID:Gamma-glutamylcysteine synthetase gene overexpression results in increased activity of the ATP-dependent glutathione S-conjugate export pump and cisplatin resistance. 748 97

To obtain cisplatin (CDDP)-resistant cells possessing the clinically induced resistance phenotype, H-460 nonsmall cell lung cancer cells (NSCLC) were pulse treated with 20, 60, 80 microM CDDP for 1 h every week, respectively. Twelve months later, three CDDP-resistant cell lines (H-460/CDDP20, H-460/CDDP60, H-460/CDDP80) were obtained that exhibit different levels of CDDP resistance (6- to 22-fold), and the possible mechanisms of resistance were studied. These resistant cells were cross-resistant to carboplatin and melphalan, but not to adriamycin or 5-fluorouracil. CDDP resistance in these cell lines appeared to be stable even after 6 months of growth in cisplatin-free medium. There was no evidence of drug accumulation differences between parental and resistant cells. Although both intracellular glutathione (GSH) content and glutathione S-transferase (GST) activity increased 1.5- to 2.5-fold in the resistant cells, only a minimal reversal of drug resistance was observed after buthionine sulfoximine (BSO) treatment, which depleted intracellular GSH levels. An enhancement of DNA repair activity was found in the resistant cell lines and played the major role in the cisplatin resistance phenotype. Using H-460/CDDP80 cells as a model, addition of a nontoxic concentration of pentoxifylline (PTX) significantly enhanced CDDP-induced cytotoxicity in a synergistic manner. Furthermore, more prominent reversal of CDDP resistance could be achieved when the resistant cells were pretreated with BSO, followed by PTX and CDDP combined treatment. This provides a rationale for combination therapy in refractory lung cancer using CDDP and two resistance modulators.
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PMID:Modulation of cisplatin resistance in acquired-resistant nonsmall cell lung cancer cells. 754 42

Conjugation of chemicals with glutathione (GSH) can lead to decreased or increased toxicity. A genetic deficiency in the GSH S-transferase mu class gene M1 has been hypothesized to lead to greater risk of lung cancer in smokers. Recently a gene deletion polymorphism involving the human theta enzyme T1 has been described: the enzyme is present in erythrocytes and can be readily assayed. A rat theta class enzyme, 5-5, has structural and catalytic similarity and the protein was expressed in the Salmonella typhimurium tester strain TA1535. Expression of the cDNA vector increased the mutagenicity of ethylene dibromide and several methylene dihalides. Mutations resulting from the known GSH S-transferase substrate 1,2-epoxy-3-(4'nitrophenoxy)propane were decreased in the presence of the transferase. Expression of transferase 5-5 increased mutations when 1,2,3,4-diepoxybutane (butadiene diepoxide), 4-bromo-1,2-epoxybutane, or 1,3-dichloracetone were added. The latter compound is a model for the putative 1,2-dibromo-3-chloropropane oxidation product 1-bromo-3-chloroacetone. These genotoxicity and genotyping assays may be of use in further studies of the roles of GSH S-transferase theta enzymes in bioactivation and detoxication and any changes in risk due to polymorphism.
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PMID:Conjugation of carcinogens by theta class glutathione s-transferases: mechanisms and relevance to variations in human risk. 758 78

The levels of several potential indicators of drug resistance were measured in tumor and corresponding normal tissue of 55 untreated patients with lung cancer. The resistance parameters include glutathione (GSH) level, activities of the enzymes glutathione transferase (GST), glutathione peroxidase (GPx) and O6-alkylguanine-DNA alkyltransferase (ATase), as well as expression of P-glycoprotein (Pgp). Median values of GSH, GST and GPx were significantly higher in tumor than in normal tissue of non-small-cell lung cancer (NSCLC) or of small-cell lung cancer (SCLC), whereas ATase was elevated in tumor tissue of NSCLC only. Pgp expression as determined by Western blotting was significantly lower in tumor than in normal tissue of NSCLC. Resistance-parameter expression did not correlate with stage of disease or age of the patients. We found a negative correlation between smoking intensity and GSH level in normal tissue. Our findings indicate that the fundamental differences in chemosensitivity between SCLC and NSCLC cannot be explained by differences in the GSH-system or in the expression of Pgp. However, the level of ATase activity may be one of the factors responsible for the difference in chemosensitivity.
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PMID:Parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA alkyltransferase and P-glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer. 796 Feb 35

Pulmonary diseases attributable to asbestos exposure constitute a significant public health burden, yet few studies have investigated potential genetic determinants of susceptibility to asbestos-related diseases. The glutathione-S-transferases are a family of conjugating enzymes that both catalyze the detoxification of a variety of potentially cytotoxic electrophilic agents and act in the generation of sulfadipeptide leukotriene inflammatory mediators. The gene encoding glutathione-S-transferase class mu (GSTM-1) is polymorphic; approximately 50% of Caucasian individuals have a homozygous deletion of this gene and do not produce functional enzyme. Glutathione-S-transferase mu (GST-mu) deficiency has been previously reported to be associated with smoking-induced lung cancer. We conducted a cross-sectional study to examine the prevalence of the homozygous deletion for the GSTM-1 gene in members of the carpentry trade occupationally exposed to asbestos. Members of the United Brotherhood of Carpenters and Joiners of America attending their 1991 National Union conference were invited to participate. Each participant was offered a chest X-ray and was asked to complete a comprehensive questionnaire and have their blood drawn. All radiographs were assessed for the presence of pneumoconiosis in a blinded fashion by a National Institute for Occupational Safety and Health-certified International Labor Office "B" reader. Individual GSTM-1 status was determined using polymerase chain reaction methods. Six hundred fifty-eight workers were studied. Of these, 80 (12.2%) had X-ray abnormalities associated with asbestos exposure. Individuals genetically deficient in GST-mu were significantly more likely to have radiographic evidence of nonmalignant asbestos-related disease than those who were not deficient (chi 2 = 5.0; P < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inherited glutathione-S-transferase deficiency is a risk factor for pulmonary asbestosis. 800 Feb 97

A doxorubicin-resistant variant of the human small-cell lung-cancer cell line N592 was selected by in vitro continuous exposure to increasing drug concentrations. The aim of this study was to examine the cross-resistance pattern, cellular pharmacokinetics of doxorubicin and expression of molecular factors of resistance. The sub-line N592/DX exhibited a multidrug-resistance phenotype, which was somewhat atypical, since it included cisplatin. Development of doxorubicin resistance could not be attributed to differential doxorubicin uptake or retention. Verapamil partially reverted doxorubicin resistance without affecting cellular pharmacokinetics. These findings are consistent with undetectable levels of mdr-1-gene expression in these cells. A molecular analysis of other putative mechanisms of multidrug resistance indicated no alterations in GSH levels or GSH-related enzymes, but a marginal reduction of topoisomerase II alpha expression in the resistant sub-line. This reduction, which was associated with an increase in topoisomerase I, does not explain the high degree of resistance. This study supports the view that alternative, unidentified mechanisms, which may be of clinical relevance, must be involved in the development of multidrug resistance of small-cell lung cancer.
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PMID:A study of cross-resistance pattern and expression of molecular markers of multidrug resistance in a human small-cell lung-cancer cell line selected with doxorubicin. 809 17


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