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)

Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.
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PMID:Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers. 1235 48

4-Methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogen believed to play a role in human lung cancer. Bioactivation of NNK involves alpha-carbon hydroxylation that could be catalyzed by cytochrome P450, hemoglobin, and lipoxygenases (LOX). In the present study, the role of LOX in NNK bioactivation was investigated. Formation of keto acid, the endpoint metabolite of alpha-methylene NNK hydroxylation, was observed in human lung cytosols incubated with 4.2 microM [5-(3)H]NNK (N = 6). Following concanavalin A affinity chromatography to enrich human lung lipoxygenase (HLLO), the fraction containing cytosolic components less LOX (fraction 1) retained the ability to bioactivate NNK. Although enriched HLLO exhibited the characteristic dioxygenase and hydroperoxidase activities, it did not bioactivate NNK. The LOX inhibitor nordihydroguaiaretic acid inhibited dioxygenase activity of HLLO by 83 +/- 19% (P < 0.05, N = 6), but did not inhibit keto acid formation in the crude cytosols (N = 6, P > 0.05). Failure of soybean LOX to catalyze NNK bioactivation supported the results observed in human lung cytosols, and failure of chemically generated alkylperoxyl radicals to bioactivate NNK further suggested that the dioxygenase activity of LOX is not likely to be involved in NNK bioactivation. Horseradish peroxidase and myeloperoxidase catalyzed NNK bioactivation were also nondetectable. Our results demonstrate that, although human lung cytosols can bioactivate NNK to form keto acid, LOX is not involved. We have attributed the ability of crude human lung cytosols to bioactivate NNK to hemoglobin. The inhibitory effect of 1-aminobenzotriazole and arachidonic acid on keto acid formation in the crude cytosols and in fraction 1, respectively (P < 0.05, N = 6), is consistent with hemoglobin-catalyzed NNK bioactivation.
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PMID:Investigation of the role of lipoxygenase in bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human lung. 1238 24

Historically, myeloperoxidase activity and subsequent production of hypochlorous acid has been associated with the killing of host-invading microorganisms (bacteria, viruses, and fungi). Currently, there is a wealth of evidence that the MPO polymorphism and enzyme activity is associated with a wide range of pathological and biological processes, including lung cancer carcinogenesis. Although the molecular epidemiology reports reviewed in this chapter are not in complete agreement on all aspects of their findings, it is evident that the MPO polymorphism contributes to the modulation of overall lung cancer risk. Four of the five molecular epidemiologic studies reviewed in this chapter utilized similar case-control study designs with quite different sources of populations. These studies all demonstrate that the MPO variant genotype modulates overall lung cancer risk. However, these studies are not in agreement regarding age and gender effects, and gene-environmental interactions. The nested case control study designed utilized by Misra et al. (35) is a valid and sound approach, but their results found no evidence of an association. Certainly, heterogeneity in study populations can contribute to the variability between these studies. Additionally, epidemiologic issues such as case-control matching and sources of control populations may contribute to the conflicting findings. Thus, the publication of inconsistent or null studies as well as other positive findings is certainly encouraged to elucidate the range of effects associated with the MPO polymorphism and lung cancer risk.
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PMID:Myeloperoxidase promoter region polymorphism and lung cancer risk. 1240 37

MPO participates in the metabolic activation of tobacco carcinogens such as PAHs. A frequent MPO -463 G-->A polymorphism in the promoter region reduces MPO transcription and has been correlated with >4-fold lower benzo[a]pyrene-DNA adduct levels in the skin of coal tar-treated patients. Four of 7 case-control studies found significantly reduced lung cancer risk associated with the A allele. Due to their different etiologies, we examined whether the MPO genotype affects histologic lung cancer types differentially. A case-control study was conducted in 625 ever-smoking lung cancer patients, including 228 adenocarcinomas, 224 SCCs, 135 SCLCs and 340 ever-smoking hospital controls. MPO genotyping was performed by capillary PCR followed by fluorescence-based melting curve analysis. Combining the MPO -463 (G/A+A/A) genotypes, a protective effect approaching significance (OR = 0.75, 95% CI 0.55-1.01) was observed when comparing all lung cancer cases to controls. Among histologic types of lung cancer, a weak protective effect was found for both adenocarcinoma (OR = 0.81, CI 0.55-1.19) and SCC (OR = 0.82, CI 0.56-1.21); a stronger and significant effect was found for SCLC (OR = 0.58, CI 0.36-0.95; p = 0.029). Our results also suggest that the MPO genotype varies among inflammatory nonmalignant lung diseases. In conclusion, our results emphasize the need for a separate analysis of lung cancer histologic types and an adjustment for inflammatory nonmalignant lung diseases in future MPO-related studies. We confirm that the MPO -463 A variant affords a protective effect against lung cancer risk in smokers, which was strongest for SCLC patients.
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PMID:Myeloperoxidase (MPO) genotype and lung cancer histologic types: the MPO -463 A allele is associated with reduced risk for small cell lung cancer in smokers. 1243 58

The myeloperoxidase (MPO) G-to-A substitution polymorphism in the promoter region of the MPO gene has been associated with a 40-70% reduction in lung cancer risk in several studies, although a recent nested case-control study disputes these findings. MPO is involved in the activation of a number of procarcinogens, including benzo(a)pyrene. The variant A allele has been shown to reduce MPO mRNA expression, thus potentially decreasing carcinogen activation. To confirm results from smaller studies, we evaluated this MPO polymorphism in 988 incident Caucasian lung cancer cases and 1128 controls. Logistic regression evaluated the association between MPO genotype and lung cancer risk, adjusting for age, gender, smoking status, time since quitting smoking, and pack-years of smoking. In the controls, the A allele frequency was 21%, and genotype distribution was in the Hardy-Weinberg equilibrium. Compared with the wild-type G/G genotype, the adjusted odds ratios for the A/A and A/G genotypes were 1.15 (95% confidence interval 0.7-1.9, P > 0.2) and 1.03 (95% confidence interval 0.8-1.3, P > 0.20), respectively. A similar lack of association was seen in analyses stratified by smoking status, median age, a number of smoking variables, disease stage, tumor grade, and histological subtype. These findings are in contrast with earlier studies suggesting a protective effect of carrying the variant A allele.
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PMID:Counterpoint: the myeloperoxidase -463G-->a polymorphism does not decrease lung cancer susceptibility in Caucasians. 1286 14

The role of myeloperoxidase (MPO), and glutathione S-transferase mu and theta (GSTM1 and GSTT1) genetic polymorphisms on lung cancer risk was investigated in 110 Caucasian patients and 119 matched controls. Single genotype variants were not significantly associated with lung cancer risk. However, inheritance of the combined GSTM1 and GSTT1 null genotypes showed a significant increase in risk (crude OR = 2.32, 95% CI = 1.01-6.04). Based on adjustment by age, gender and smoking history, the MPO GA interacted with the presence of GSTM1 and GSTT1 genotypes to significantly reduce the risk (OR = 0.17, 95% CI = 0.03-0.98). From the chromosome aberration (CA) study in a subgroup of 79 patients and 69 matched controls, patients had significantly more CA than the controls. Among the patients, GSTM1 null was associated with a significant increase of CA and MPO AA was associated with a significant decrease of CA compared to their respective wild-type genotypes. After stratifying by smoking history (< or = and > 40 pack-years) and genotype, patients still had significantly more CA than the respective controls in most genotype categories. This indicates that the patients had additional contributing factors such as other susceptibility genes and/or different styles of smoking compared with the controls. In conclusion, our study indicates that CA is a useful biomarker to show the functional characteristics of genotypes and the interactive effects from combined genotypes. Therefore, our study strengthens the combined use of genotype and biomarkers for genetic susceptibility to environmental cancer.
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PMID:Combined effect of MPO, GSTM1 and GSTT1 polymorphisms on chromosome aberrations and lung cancer risk. 1462 95

The myeloperoxidase (MPO) -463G-->A genetic polymorphism is associated with a reduced risk for lung cancer, but the underlying mechanism is not yet elucidated. Therefore, the impact of this polymorphism on MPO activity and lipophilic DNA adducts was studied in respectively bronchoalveolar lavage (BAL) fluid and cells, from 106 smoking Caucasian lung patients. MPO activity was determined spectrophotometrically, aromatic DNA adducts by (32)P-postlabeling and MPO genotypes by RFLP analysis. Frequencies of MPO -463AA (13%), MPO -463AG (36%), and MPO -463GG (51%) were in line with earlier observations. MPO activity/neutrophil was lower in MPO -463AA (median 0.04 pU/cell) than in MPO -463AG (median 0.07 pU/cell) and MPO -463GG (median 0.14 pU/cell; P = 0.059) individuals. DNA adducts in BAL cells were measured in 11 MPO -463AA subjects and equal numbers of MPO -463AG and MPO -463GG subjects matched for smoking, age, gender, and clinical diagnosis. DNA adduct levels in MPO -463AA individuals (median 0.62 adducts/10(8) nucleotides) were lower than in MPO -463AG (median 1.51 adducts/10(8) nucleotides) and MPO -463GG (median 3.26 adducts/10(8) nucleotides; P = 0.003) subjects. Overall, no significant correlation was observed between amount of inhaled tar/day and DNA adduct levels. However, correlations improved considerably on grouping according to the MPO genotype; MPO -463AA subjects were the least responsive (R(2) = 0.73, slope = 0.4, P = 0.01) followed by MPO -463AG subjects (R(2) = 0.70, slope = 1.3, P = 0.01) and MPO -463GG patients (R(2) = 0.67, slope = 2.8, P = 0.02). These data demonstrate that MPO -463AA/AG genotypes are associated with (a) reduced MPO activity in BAL fluid and (b) reduced smoking-related DNA adduct levels in BAL cells in a gene-dose manner. These data provide a plausible biological explanation for the reduced risk for lung cancer as observed in MPO -463AA/AG compared with MPO -463GG subjects.
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PMID:Myeloperoxidase (MPO) -463G->A reduces MPO activity and DNA adduct levels in bronchoalveolar lavages of smokers. 1515 16

We have previously investigated the role of polymorphic chemical metabolizing genes in the susceptibility to the development of lung cancer using 110 primary lung cancer patients and 119 matched smoker controls. Together with data from the present study on DNA repair genes, we did not observe significant associations between any single variant genotype for several DNA-repair and chemical-metabolizing genes (XPD [or ERCC2], XRCC1, XRCC3, GSTM1, GSTT1, MPO, and mEH [or EPHX1]) and lung cancer. In the present study, we have further evaluated a nested group of 79 patients and 69 matched controls, and observed that increased chromosome aberrations (CAs) were associated with variant DNA-repair genotypes among both the patient and the control groups, with a significant increase for individuals having the XPD Lys/Gln + Gln/Gln genotypes (P = 0.046). Patients often had significantly increased CAs compared with controls with the same DNA-repair genotype and with similar cigarette smoking habits (< or =40 pack-years or >40 pack-years). Analyses of interactions between the DNA-repair and chemical-metabolizing genes indicated that the most significant interactions were between the repair genotypes and the GSTM1/T1 null genotypes. Significant increases in CA from the interactions were often observed among patients with < or =40 pack-years, but not among those with >40 pack-years. Since some variant DNA-repair genotypes have functional deficits for DNA repair, the association between variant DNA-repair genotypes and increased CAs suggests a risk mechanism for the development of lung cancer, with the DNA-repair genotypes interacting with variant chemical metabolizing genotypes to further increase the risk. The observation that patients had significantly increased CA frequencies compared with controls, irrespective of genotype, suggests that patients have additional factors that contribute to the development of lung cancer.
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PMID:Polymorphisms in DNA repair genes, chromosome aberrations, and lung cancer. 1519 49

Tumor liberated protein (TLP) is a protein that can be used to reveal the early development of a tumor. Besides being formed in the tumor, TLP is released in the blood when a patient starts producing cancer cells, which in turn enables the physician to intervene at a stage when the cancer is operable. To date, the available studies of tumor markers in lung cancer patients are CEA, NSE, TPA, Chromogranine, CA125, CA19-9, and Cyfra 21-1. The sensitivity and specificity for serum markers ranges between 50 and 90%, depending on the study and the clinical samples analyzed. Most of these markers show an increased rate of positivity as the stage advances. There are very limited data on TLP to draw any firm conclusion regarding the diagnostic value of this marker. TLP has been detected in 53.1% of non-small cell lung cancer (NSCLC) patients (N = 534) with 75% being positive in the early stage (stage I) and dropping to 45% in the late stage (stage IV). However, 7.6% blood donor sera and 17.4% chronic lung disease sera have also tested positive. In a confirmation study, the specificity was 89.94% and the sensibility was 63.63% from stage III to IV NSCLC patients. In an initial study of TLP as a marker for early detection in stage I, NSCLC patients showed a sensitivity of 66.7% and a specificity of 80% for TLP compared to a sensitivity of 33.3% for CA19-9, 11.1% for Cyfra 21-1 and CA125, and 0% for CEA; the specificity for all four of the latter markers was 100%. Using immunohistochemical analysis with peroxidase anti-peroxidase (PAP), we observed that NSCLC cells were positive; we used the specific rabbit antiserum to TLP, which turned out negative in the presence of 1 mg/ml of the synthetized peptide. The pre-serum was also negative. The same reactivity was found early in the modified epithelial cells of interstitial lung fibrosis and might be a predictive marker of cell transformation. The site of the peroxidase positivity was cytoplasmic, of diffuse and/or granular type.
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PMID:Early diagnosis of lung cancer by detection of tumor liberated protein. 1538 37

Loss of antioxidant/oxidant homeostasis perpetuates inflammation in the lungs and may contribute to the development of COPD and lung cancer. Cigarette smoke (CS) is a primary source of airway oxidative stress and recruits inflammatory cells into smokers' lungs. However, whether these consequences are attributable to a specific or the collective fraction of CS is unknown. We investigated whether the particulate or the gas phase of CS would alter expression of the antioxidant enzymes MnSOD and NQO1 or CINC-1. Sprague Dawley rats were exposed to sham (n = 10) or the particulate phase (PP; n = 10) or gas phase (n = 10) of a Kentucky reference cigarette (1R4F) for 2 h/d for 28 d, after which animals were sacrificed and the lower left lobe of the lung was removed. Immunoblots for SOD and NQO1 revealed that lungs exposed to PP had higher MnSOD/actin and NQO1/actin ratios than either sham-or gas phase-treated animals. In contrast, CuZnSOD remained unchanged. In PP-exposed animals, CINC-1 was 3-fold higher than in sham-exposed animals. The increases in MnSOD and NQO1 protein were associated with increases in total SOD, NQO1, and MPO activities. These data provide evidence that the PP of CS alters oxidant/antioxidant homeostasis in the lungs and participates in the pathogenesis of CS-induced lung diseases such as COPD and cancer.
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PMID:Particulate phase cigarette smoke increases MnSOD, NQO1, and CINC-1 in rat lungs. 1547 4


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