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)

The human Mu class Glutathione S-Transferases is a family of genes encoding phase II detoxifying enzymes thus playing a significant role in the detoxification of potential carcinogens. While there are many contradicting reports on the association of GSTM1 polymorphisms and cancer development, no studies exist to date describing polymorphisms in GSTM4. We have identified a new C-T polymorphism in intron 6 of the GSTM4 gene (T2517C, Genebank sequence accession number X68677) and termed the allele carrying T at this position allele *A and the allele carrying C, allele *B. Screening a population sample in Merseyside, England, revealed 23 carriers of the *B allele out of 156 healthy control individuals but only 12 carriers of the *B allele out of 163 individuals with lung cancer (O.R.=2.23, Fisher's test P=0.026). The polymorphism did not demonstrate any associations with tumour type, gender, and age at presentation. This is the first report on the implication of a polymorphism in the GSTM4 gene in lung cancer risk. Further studies are required to investigate the relation of this polymorphism to cancer risk to substantiate these findings.
Lung Cancer 2002 Aug
PMID:A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer. 1214 Jan 36

Trichloroethylene (TCE) and perchloroethylene (PERC) are volatile organic compounds (VOCs) that are primarily inhaled through the respiratory system. The aim of this study was to elucidate the role of glutathione (GSH) and p53 in TCE- and PERC-induced lung toxicity. Human lung adenocarcinoma cells NCI-H460 (p53-wild-type) have constitutively lower levels of GSH than NCI-H1299 (p53-null) cells. The results showed that exposure to vapor TCE and PERC produced a dose-dependent and more pronounced accumulation of H(2)O(2) in p53-WT H460 than p53-null H1299 cells. The accumulation of H(2)O(2) was accompanied by severe cellular damage, as indicated by the significant increase of lipid peroxidation and apoptosis in p53-WT H460 cells, but not p53-null H1299 cells. Cotreatment of p53-WT H460 cells with free radical scavengers, such as D-mannitol, uric acid, and sodium selenite, significantly attenuated the TCE- or PERC-induced lipid peroxidation. In contrast, depletion of GSH in p53-null H1299 cells enhanced TCE- or PERC-induced lipid peroxidation. The levels of p53 and Bax proteins were elevated, while Bcl-2 protein was downregulated in TCE- or PERC-treated p53-WT H460 cells. Activity of caspase 3, the apoptotic executioner, was also significantly enhanced in TCE- or PERC-treated cells. These data suggest that, in human lung cancer cells, GSH plays a vital role in the protection of TCE- and PERC-induced oxidative stress and apoptosis, which may be mediated through a p53-dependent pathway.
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PMID:Possible involvement of glutathione and p53 in trichloroethylene- and perchloroethylene-induced lipid peroxidation and apoptosis in human lung cancer cells. 1216 Sep 29

Chronic exposure to low levels of arsenic can cause lung cancer. However, the cellular and molecular mechanisms for lung cell transformation in response to arsenic are not known. These studies investigated the hypothesis that low levels of arsenic increase intracellular oxidant levels, promote production of mitogenic transcription factors and antioxidant enzymes. Initially, arsenic decreased GSH cellular level and rapidly increased to 280% of GSH level in nonexposed lung cells in 24 h. Buthionine sulfoximine (BSO) potentiated the arsenic toxicity of lung epithelial cells (LEC). Exposure of LEC to 5 microM arsenite cause time-dependent increase in gamma-glutamylcysteine synthetase (gamma-GCS) expression. Our data demonstrated that arsenic induced the heavy subunit of gamma-GCS (gamma-GCS-HS) mRNA levels as early as 4 h as compared to the control level. It significantly increased (sixfolds) gamma-GCS-HS mRNA expression after 8 h of treatment. The activation of AP-1 transcription factors may also play a regulatory role in this process. Significant elevations in c-fos and c-jun mRNA levels were observed within 30 min after exposure to arsenic and by enhancement of AP-1 DNA binding activity and transactivation activity. Responsiveness of LEC to oxidative stress caused by arsenic exposure was further evaluated with mobility shift assay involving redox-sensitive transcription factor NF-kappa B. The specificity of binding was verified by an antibody-supershift. The NF-kappa B DNA binding activities increased more than twofold 30 min after exposure to arsenic and returned to control levels after 4 h of treatment. It remains to be determined whether NF-kappa B plays a role in the As-induced apoptosis or alternatively in attempting to protect the cells from As-induced cell death by upregulating the expression of resistance factors.
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PMID:Arsenic induces oxidative stress and activates stress gene expressions in cultured lung epithelial cells. 1221 Jul 19

ZD0473 is a new generation platinum agent that, in preclinical studies, shows evidence of an extended spectrum of anti-tumor activity and overcomes platinum resistance mechanisms. The drug contains a bulky methylpyridine ligand at its platinum center, which is responsible for its ability to overcome platinum resistance. We examined the growth inhibitory effects of ZD0473 in human lung cancer cell lines resistant to cisplatin in vitro. Four cisplatin resistant human lung cancer cell lines (PC-14/CDDP, SBC-3/CDDP, PC-9/CDDP, H69/CDDP) showed the expected resistance to cisplatin but were non-cross, or much less, resistant to ZD0473, as determined by an MTT assay. A reduction in the intracellular accumulation of cisplatin, but not of ZD0473, was observed in the PC-14/CDDP cells compared with the levels in PC-14 parental cells. The reduction in cisplatin accumulation is considered a major mechanism of the acquired cisplatin resistance in PC-14/CDDP cells. Therefore, the increase in platinum accumulation is considered a possible mechanism underlying the activity of ZD0473 in cisplatin-resistant cells. Glutathione-mediated resistance to cisplatin was also overcome by ZD0473 in PC-14/CDDP cells. In addition, we showed that the intraperitoneal administration of ZD0473 at its maximum tolerable dose in mice produced a marked in vivo antitumor activity against cisplatin-resistant PC-14/CDDP tumors. These results suggest that ZD0473 may be a potent agent in human lung cancer cells with multifactorial cisplatin resistance.
Lung Cancer 2002 Oct
PMID:Non-cross resistance of ZD0473 in acquired cisplatin-resistant lung cancer cell lines. 1236 92

The synergistic interaction of two ligands (INH2BP and the prodrug INO2BA) of PARP I has been demonstrated for two human leukemia cell lines (855-2 and HL-60), for a human lung cancer cell (A549) and for Eras 20 cancer cells. Synergism was calculated using kinetic combination constants based on cell multiplication rates. Reducing cellular GSH content by BSO strongly augmented synergism, an effect partly explained by the removal of C-NO scavenging (by GSH). However, INH2BP action was augmented by BSO, an effect most probably explained by the sensitization of the cell to apoptosis by GSH removal.
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PMID:Synergistic anticancer action of reversibly and irreversibly acting ligands of poly (ADP-ribose) polymerase. 1252 76

Glutathione transferases (GSTs), a multiple gene family of phase II enzymes, catalyze detoxifying endogenous reactions with glutathione and protect cellular macromolecules from damage caused by cytotoxic and carcinogenic agents. Glutathione S-transferase p1 (GSTP1), the most abundant GST isoform in the lung, metabolizes numerous carcinogenic compounds including benzo[a]pyrene, a tobacco carcinogen. Previous studies suggest that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have functional effects on the GST gene product resulting in reduced enzyme activity. Individuals with reduced GST enzymatic activity may be at a greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. Utilizing a hospital-based case-control study, we investigated the association between GSTP1 polymorphisms at exons 5 and 6 with lung cancer risk. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to successfully genotype the GSTP1 exons 5 and 6 polymorphism in 582 Caucasian lung cancer cases and 600 frequency matched Caucasian controls. There was no association between the exon 5 variant genotypes (A/G+G/G) and overall lung cancer risk (OR=1.09; 95% CI 0.82-1.45) nor when stratified by age, gender, and smoking status. However, the exon 6 variant genotypes (C/T+T/T) were associated with a statistically significant elevated lung cancer risk (OR=1.40; 95% CI 1.06-1.92). Additionally, there was an increase in lung cancer risk for the exon 6 variant genotypes in younger individuals (<62 years) (OR=1.63; 95% C.I. 1.07-2.49) but no effect in older individuals (OR=1.14; 95% CI 0.72-1.81). A statistically significant increased risk of lung cancer was also observed for the exon 6 variant genotypes among men (OR=2.17; 95% CI 1.41-3.33), but not among women (OR=0.80; 95% CI 0.51-1.28). Among ever smokers, the exon 6 variant genotypes were associated with an elevated lung cancer risk (OR=1.58; 95% CI 1.14-2.19), which was not evident for never smokers (OR=0.53; 95% CI 0.21-1.33). These data demonstrate that the GSTP1 exon 6 polymorphism, but not the exon 5 polymorphism, is associated with lung cancer risk that is especially evident in men, younger individuals, and ever smokers.
Lung Cancer 2003 Apr
PMID:Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: a case-control study. 1266 4

We assessed the association of three genetic polymorphisms, NAD(P)H quinone oxidoreductase (NQO1), Glutathione-S-transferase P1 (GSTP1), and manganese superoxide dismutase (MnSOD), with lung cancer risk in 198 cases and 332 controls in Taiwan. Overall, NQO1 and MnSOD polymorphisms were not associated with an increased risk of lung cancer. Individuals carrying variant alleles of GSTP1 were at higher risk of squamous cell lung carcinoma (odds ratio, 1.63; 95% confidence interval, 0.96-2.74). When the groups were further stratified by smoking status following gender and histological type, the wild-type NQO1 was associated with lung adenocarcinoma among smokers but not among nonsmokers (odds ratio, 2.49; 95% confidence interval, 1.17-5.32). These results suggest that NQO1 plays a role in the development of cigarette smoking-associated lung adenocarcinoma. In addition, GSTP1 polymorphism was associated with the risk of squamous cell lung carcinoma in Taiwan.
Lung Cancer 2003 May
PMID:Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan. 1271 Nov 12

Glutathione S-transferases (GSTs) are a family of enzymes that detoxify hydrophobic electrophiles, including polycyclic aromatic hydrocarbon carcinogens that have been implicated in the pathogenesis of lung cancer. The GSTM1 gene within the mu class of human GSTs has been shown to be polymorphic, with individuals who are homozygous for a null allele having the GSTM1-null genotype. Individuals with the GSTM1-null genotype are deficient in both the GSTM1 and GSTM3 isoenzymes in the lung. A number of epidemiological studies have been conducted to assess the association between the GSTM1-null genotype and the risk of lung cancer. Although there have been conflicting reports regarding this relationship, the current weight of evidence indicates that the GSTM1-null genotype is probably associated with a modest increase in the risk of lung cancer. This risk appears to be greater in African-American and Asian populations than in Caucasians. Recent investigations have shown that the GSTM1-null genotype combined with CYP1A1, NAT2, or GSTP1 polymorphisms confers a greater risk of lung cancer than the GSTM1-null genotype alone. Future investigations should focus on assessing the risk of lung cancer related to multiple combinations of genetic polymorphisms that may identify individuals who are at high risk for developing lung cancer with a greater degree of certainty than is currently possible. This could lead to new clinical strategies for counseling, risk reduction and the detection of lung at an early and potentially curable stage.
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PMID:Glutathione S-transferase M1 polymorphism and the risk of lung cancer. 1289 85

Glutathione S-transferases are possibly related to the detoxification of many xenobiotics involved in the etiology of cancer. To investigate the role of the glutathione S-transferase M1 deletion (GSTM1-null) in lung cancer, the polymerase chain reaction was used to determine the GSTM1 genotypes of lung cancer patients (n=101) and hospital (n=206) in a Turkish population. The prevalence of the GSTM1-null genotype in the case group was 48%, compared to 18% in the control group, giving an odds ratio (OR) of 4.14 (95% confidence interval [CI]=2.36-7.27). The analysis of patients by histologic type of lung cancer (10% adenocarcinoma, 43% squamous cell carcinoma, 26% small cell carcinoma, and 11% large cell carcinoma) showed no association between histopathologic type of lung cancer and GSTM1-null genotype. When the interaction between the GSTM1-null genotype and smoking status was analyzed, among the 67 smokers, the GSTM1-null genotype was found in 37 (55%) with an OR of 2.58 (95% CI=1.00-6.73) indicating a significant association. However, no association was found between smoking exposure (<30 and > or =30 packs/year) and GSTM1-null genotype. We conclude that, in this study the null GSTM1 genotype is an independent risk factor for the development of lung cancer for Turkish population.
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PMID:Strong association between the GSTM1-null genotype and lung cancer in a Turkish population. 1455 46

The utility of dominant acting proapoptotic molecules to induce cell death in cancer cells is being evaluated in preclinical studies and clinical trials. We recently developed a binary adenoviral expression system to enable the efficient gene transfer of Bax and other proapoptotic molecules. Using this system, overexpression of Bax protein in four non-small-cell lung cancer (NSCLC) cell lines, H1299, A549, H226 and H322, was evaluated. The H322 line exhibited significant resistance to Bax-induced cell death compared to the other cell lines. H322 cells had the highest level of glutathione (GSH). GSH levels were significantly decreased following buthionine sulfoximine treatment and this coincided with enhanced apoptosis induction by Ad-Bax in H322 cells. GSH depletion enhanced Bax protein translocation to mitochondrial membranes. These findings suggest that the redox status may be a determinant of Bax-mediated cell death and that manipulation of intracellular thiols may sensitize cells to apoptosis by facilitating Bax insertion into mitochondrial membranes.
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PMID:GSH depletion enhances adenoviral bax-induced apoptosis in lung cancer cells. 1500 33


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