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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of (pre)carcinogens that it is astonishing that not every heavy smoker becomes a victim of malignancy. This points to the interindividual variability in susceptibility to carcinogens; several lines of evidence suggest that metabolic factors are involved in such variability. Metabolism of carcinogens as well as the subsequent (multi)steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics. N-Acetylcysteine (NAC), an aminothiol and synthetic precursor of intracellular cysteine and GSH, has been used for many years in Europe as a mucolytic drug. Clinically, it is a safe agent without major side effects and has been considered to have a place in cancer prevention, too. The antimutagenic and anticarcinogenic properties of NAC could be ascribed to multiple protective mechanisms, such as NAC nucleophilicity, antioxidant activity, its ability to act as a precursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer. 853 5

In the case of lung cancer induced by chemical carcinogens, cellular processes of metabolic activation and deactivation of these substances play a particular role. The involvement of glutathione--S-transferase in the process of deactivation of active metabolites draws special attention. Cellular activity of these enzymes is a significant factor which can define individual susceptibility to carcinogenic effect of occupational and environmental carcinogens. Glutathione--S-transferase catalyses the reaction of binding glutathione with a great number of pharmacologically active substances, including also those with genotoxic properties. These reactions protect cells against toxic and genotoxic effect of exo- and endogenous substances. They prevent among others, from producing adducts by genotoxic substances with macromolecules. Some of glutathione--S-transferases (the so-called ligands) act as proteins which bind and transport organic ligands in cells (bilirubin, steroid metabolites, bile acids). To date studies have not confirmed uni-vocally that low activity of glutathione--S-transferases be one of the reasons for an increased incidence of lung cancer. Observations of persons with phenotype of a low activity of glutathione--S-transferase (GSTM1-0) have indicated that the incidence of lung cancer is significantly higher among them than in persons with phenotype of normal activity of this enzyme. These observations, however, have not been confirmed by an analysis of relationship between the incidence of lung cancer and the genotype of low and normal activity of glutathione--S-transferase.
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PMID:[Glutathione S-transferase as a metabolic biomarker for predisposition to lung neoplasms induced by chemical carcinogens]. 855 56

Occupational exposure to silica has often been associated with the development of pulmonary fibrosis and, occasionally, lung cancer. Their development may be mediated by oxidant-induced cellular injury. The short- and long-term effects of a single intratracheal instillation of silica in rats (10 mg/200 microliters/saline per rat) was assessed by measuring 8-hydroxy-2'-deoxyguanosine (oh8dG) levels in lung tissue and peripheral blood leukocytes. Cell differentials, reduced glutathione (GSH), and superoxide dismutase (SOD), lipid peroxide, and total phospholipids in peripheral blood and/or bronchoalveolar lavage fluid (BALF) were also measured. The pulmonary oh8dG levels increased approximately 2.24- 2.86-fold from 1 to 5 days after exposure to silica. It was still elevated 1 and 4 weeks after installation, but the difference was no longer statistically significant. The oh8dG levels in peripheral blood leukocytes were never significantly different, but they were generally higher than in the controls. The low SOD levels in the BALF of exposed rats in the early stage and the higher GSH levels in the late stage may represent protective reactions against the generation of oxygen species. A significant increase in oh8dG levels in lung tissue suggested the possible carcinogenicity of silica.
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PMID:Oxidative DNA damage induced by silica in vivo. 860 69

A phase II trial of menadione [2.5 gm/m2 as a continuous intravenous (i.v.) infusion over 48 hours] followed by mitomycin C (10-20 mg/m2 i.v. bolus) administered every 4 to 6 weeks was performed in 23 patients with advanced lung cancer. Menadione, a vitamin K analog which lowers intracellular pools of reduced glutathione (GSH), was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating agent chemotherapy. The median age of patients entered on this trial was 62 years; performance status ranged from 60-90%. Two of the 23 patients (9%; 95% confidence interval, 1% to 28%) had objective responses lasting 3.5 months and 13 months respectively, while 4 additional patients developed short unconfirmed responses (lacking follow-up response data to estimate response duration). Median survival for all patients was 5.5 months. Treatment with mitomycin C and menadione was well tolerated except for hematologic toxicity and cardiac events of unclear relationship to the study drugs. Thirty-one percent of treatment courses were complicated by grade 3 or 4 hematologic toxicity including one episode of hemolytic anemia. One patient developed interstitial pneumonitis. Two patients developed a decrease in left ventricular ejection fraction: one patient remained asymptomatic, but the other patient developed congestive heart failure. Although only 9% of patients had confirmed objective responses, 28% (5 of 18) of the patients with non-small cell lung cancer demonstrated biological activity (tumor regression fulfilling the criteria for objective response on a single occasion but 3 patients lacking a follow-up measurement to document response duration) to this combination of mitomycin C and menadione. We conclude that further studies of chemomodulation in non-small cell lung cancer are appropriate.
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PMID:Mitomycin C and menadione for the treatment of lung cancer: a phase II trial. 861 79

The 190-kDa multidrug resistance protein (MRP) has recently been associated with the transport of cysteinyl leukotrienes and several glutathione (GSH) S-conjugates. In the present study, we have examined the transport of leukotriene C4 (LTC4) in membrane vesicles from MRP-transfected HeLa cells (T14), as well as drug-selected H69AR lung cancer cells which express high levels of MRP. V(max) and K(m) values for LTC4 transport by membrane vesicles from T14 cells were 529 +/- 176 pmol mg(-1) min(-1) and 105 +/- 31 nM, respectively. At 50 nM LTC4, the K(m) (ATP) was 70 micron. Transport in T14 vesicles was osmotically-sensitive and was supported by various nucleoside triphosphates but not by non- or slowly-hydrolyzable ATP analogs. LTC4 transport rates in membrane vesicles derived from H69AR cells and their parental and revertant variants were consistent with their relative levels of MRP expression. A 190-kDa protein in T14 membrane vesicles was photolabeled by [3H]LTC4 and immunoprecipitation with MRP-specific monoclonal antibodies (mAbs) confirmed that this protein was MRP. LTC4 transport was inhibited by an MRP-specific mAb (QCRL-3) directed against an intracellular conformational epitope of MRP, but not by a mAb (QCRL-1) which recognizes a linear epitope. Photolabeling with [3H]LTC4 was also inhibitable by mAb QCRL-3 but not mAb QCRL-1. GSH did not inhibit LTC4 transport. However, the ability of alkylated GSH derivatives to inhibit transport increased markedly with the length of the alkyl group. S-Decylglutathione was a potent competitive inhibitor of [3H]LTC4 transport (K(i(app)) 116 nM), suggesting that the two compounds bind to the same, or closely related, site(s) on MRP. Chemotherapeutic agents including colchicine, doxorubicin, and daunorubicin were poor inhibitors of [3H]LTC4 transport. Taxol, VP-16, vincristine, and vinblastine were also poor inhibitors of LTC4 transport but inhibition by these compounds was enhanced by GSH. Uptake of [3H]vincristine into T14 membrane vesicles in the absence of GSH was low and not dependent on ATP. However, in the presence of GSH, ATP-dependent vincristine transport was observed. Levels of transport increased with concentrations of GSH up to 5 mM. The identification of an MRP-specific mAb that inhibits LTC4 transport and prevents photolabeling of MRP by LTC4, provides conclusive evidence of the ability of MRP to transport cysteinyl leukotrienes. Our studies also demonstrate that MRP is capable of mediating ATP-dependent transport of vincristine and that transport is GSH-dependent.
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PMID:Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. Demonstration of glutathione-dependent vincristine transport. 862 43

Cells exposed to calcein acetoxymethyl ester (calcein AM) in the growth medium become fluorescent following cleavage of calcein AM by cellular esterases to produce the fluorescent derivative calcein. It has previously been shown by others that multidrug resistant cells which overexpress P-glycoprotein accumulate much less fluorescent calcein than the corresponding parental cells. We have now examined the transport of calcein in multidrug resistant cells which overexpress an alternative transporter, the multidrug resistance-associated protein (MRP). Accumulation of calcein fluorescence was greatly reduced in the MRP-overexpressing human lung cancer cell lines COR-L23/R and MOR/R compared with their parental lines. Energy depletion resulted in a considerably increased accumulation in the resistant lines. Treatment of resistant cells with buthionine sulfoximine (BSO), which depletes cellular glutathione (GSH), did not affect calcein accumulation, in marked contrast to our previous results for daunorubicin or the fluorescent probe rhodamine 123. Genistein, verapamil, cyclosporin A and ouabain were also each able to modify, to some extent, accumulation of daunorubicin, whilst having essentially no effect on calcein accumulation. However, the organic anion transport inhibitor probenecid was able to increase accumulation of both calcein and daunorubicin in the resistant cells. Genistein and verapamil treatment preferentially reduced the GSH content of resistant cells, whilst probenecid did not. However, probenecid caused a clear decrease in release of GSH from resistant cells into the medium.
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PMID:On the relationship between the probenecid-sensitive transport of daunorubicin or calcein and the glutathione status of cells overexpressing the multidrug resistance-associated protein (MRP). 884 45

An international symposium entitled Chemical Carcinogenesis, Mutagenesis and Teratogenesis: a Tribute to James and Elizabeth Miller was held in Toronto, Ont., July 19, 1994. This symposium theme was discussed in the presence of James Miller, 79 years young, who with his wife, Elizabeth Miller (1920-1987), are considered to be the pioneers of this medical and environmental toxicology research field. It is generally believed that the susceptibility of an individual to chemical carcinogenesis or teratogenesis varies considerably depending upon their genetic makeup, diet, lifestyle, and their environmental exposure. One goal of the research discussed at this symposium was an examination of the role of the enzymes involved in the metabolic activation and detoxification of carcinogens and teratogens. The interindividual variabilities in the levels and activity of these enzymes could contribute to the susceptibility of the individual to chemical carcinogens or teratogens. At the symposium evidence was presented indicating that theta-class glutathione (GSH) S-transferase levels activate dihalomethanes and could therefore initiate the carcinogenic response to butadiene and 1,2-dibromo-3-chloropropane. The dramatic genetic polymorphism of this class of GSH S-transferase could thereby contribute to the individual's susceptibility to these carcinogens. Similarly, the GSH S-transferase and GSH levels in the embryo and yolk sac that are determined during organogenesis could also be important factors in determining the susceptibility of the embryo to teratogens. The levels of cytochrome P450 1A2, aromatic amine N-acetyltransferases, and sulfotransferases could also determine the susceptibility of the individual to carcinogenic arylamines. Accordingly, an Ames tester strain was described that was genetically engineered so as to express both aromatic amine N-acetyltransferase and human cytochrome P450 1A2. This should prove useful for predicting which arylamines are likely to be carcinogenic to humans. Nonsteroidal anti-inflammatory drugs may also prove useful in inhibiting the cytochrome P450s that activate the nitrosamines found in tobacco smoke suspected to cause lung cancer. Finally, the sulfotransferase isoforms involved in the metabolic activation of carcinogenic arylamines were identified.
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PMID:Chemical carcinogenesis, mutagenesis, and teratogenesis. 888 21

Glutathione (GSH) is one of the key components of the lung antioxidant defenses. Chronic smokers have higher GSH concentrations in their epithelial lining fluid than do nonsmokers. The aim of this study was to compare antioxidant concentrations in epithelial lining fluid (ELF) from nonsmokers, smokers with, and smokers without non-small-cell lung cancer. The study found that GSH in ELF from patients with lung cancer was significantly greater than in ELF from smokers and nonsmokers, at 1,485.5 +/- 208, 544 +/- 97.6 microM, and 339.3 +/- 112 microM, respectively (p < 0.05). In contrast, superoxide dismutase (SOD) was lower in ELF from patients with lung cancer than in that from smokers and nonsmokers, at 3.52 +/- 0.99, 30.82 +/- 8.2, and 43.91 +/- 10.1 U/ml, respectively (p < 0.05). Spontaneous superoxide anion release by adherent alveolar macrophages (AM) showed no difference between smokers with and without lung cancer. These data indicate that patients with lung cancer have marked modifications in their ELF antioxidant defenses by comparison with those of smokers. It is difficult to distinguish whether changed antioxidant status is a primary disturbance involved in the cancer process or whether it is a consequence of the neoplastic changes in malignancy.
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PMID:Antioxidant activity in bronchoalveolar lavage fluid from patients with lung cancer. 897 Mar 59

Cigarette smoking has been shown to be a major risk factor for cardiovascular disease, lung cancer, and respiratory diseases. Due to its high content of oxidants, the cigarette smoke is bound to cause a prooxidant/antioxidant imbalance in the blood plasma and tissues of smokers. The study groups were selected from an apparently healthy population living in urban areas, comprising 200 subjects aged 18 to 80 years, half of whom were smokers. In smokers aged 18 to 45 years, the changes of the plasma prooxidant parameters (i.e., lipid peroxides, leukocyte activation, and the antioxidant ones [thiol concentration, total antioxidant capacity]) were not significantly different from those of the age-matched controls, whereas in the 46 to 80 age group they were. In smokers, both antioxidant erythrocyte enzymes, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), exhibited increased activity in the 18 to 45 age group and decreased activity in the 46 to 80 age group. The differences in enzyme activity between the smoking and nonsmoking groups were highly significant for SOD in all ages, whereas for GSH-Px the difference in activity was significant only in the case of older smokers. These findings would suggest that a process of adaptation takes place in younger smokers, in whom the antioxidant systems are able to counteract the oxidant factors, while in older smokers this process is no longer occurring and the plasma and tissues are under permanent oxidative stress. Our results clearly demonstrated that a prooxidant/antioxidant imbalance exists in the blood of smokers, and the determination of leukocytes stimulation index may be a useful and simple way of assessing the oxidative stress status of these individuals. A hypothesis regarding a possible mechanism linking cigarette smoking to the development of coronary heart disease is presented.
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PMID:Cigarette smoking causes biochemical changes in blood that are suggestive of oxidative stress: a case-control study. 900 95

The effect of x-rays on GSH and GSSG levels in blood was studied in mice and humans. An HPLC method that we recently developed was applied to accurately determine GSSG levels in blood. The glutathione redox status (GSH/GSSG) decreases after irradiation. This effect is mainly due to an increase in GSSG levels. Mice received single fraction radiotherapy, at total doses of 1.0 to 7.0 Gy. Changes in GSSG in mouse blood can be detected 10 min after irradiation and last for 6 h within a range of 2.0-7.0 Gy. The highest levels of GSSG (20.1 +/- 2.9 microM), a 4.7-fold increase as compared with controls) in mouse blood are found 2 h after radiation exposure (5 Gy). Breast and lung cancer patients received fractionated radiotherapy at total doses of 50.0 or 60.0 Gy, respectively. GSH/GSSG also decreases in humans in a dose-response fashion. Two reasons may explain the radiation-induced increase in blood GSSG: (a) the reaction of GSH with radiation-induced free radicals resulting in the formation of thyl radicals that react to produce GSSG; and (b) an increase of GSSG release from different organs (e.g., the liver) into the blood. Our results indicate that the glutathione redox ratio in blood can be used as an index of radiation-induced oxidative stress.
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PMID:Blood glutathione as an index of radiation-induced oxidative stress in mice and humans. 909 94


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