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)

Recent studies have suggested that glutathione S-transferase pi (GST-pi) may play a role in determining tumor sensitivities to cytotoxic drugs. In order to better understand the role of this enzyme in chemo- and/or radioresistance of lung cancer cells, we examined whether introduction of GST-pi cDNA into a chemo- and radiosensitive lung cancer cell line altered its sensitivities to various chemotherapeutic agents and/or ionizing radiation, which are often used in the management of lung cancers. Modestly increased resistance of the GST-pi transfectants preferentially to sublethal damage caused by ionizing radiation as well as to adriamycin (ADM) was observed. In contrast, resistances to cisplatin (CDDP), etoposide (VP-16), irinotecan hydrochloride (CPT-11) and paclitaxel were virtually unaltered. These results suggest that GST-pi may not play a major role in chemo- and radioresistance of lung cancers, although it could afford selective and limited protection against ADM- and ionizing radiation-induced damage.
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PMID:Modification of chemo-radiosensitivity of a human lung cancer cell line by introduction of the glutathione S-transferase pi gene. 855 60

A total of 175 lung cancer patients and 104 controls were detected for GST mu gene using PCR technique. The results showed that the GST mu gene deletion rate in lung cancer patients was 71.4%, which was significantly higher than the controls, 51.9%. Analysis according to pathological classification of lung cancer indicated that the GST mu gene deletion rate in all three kinds of pathological types-squamous, adenocarcinoma and small cell carcinoma, were markedly higher than that of controls, especially for small cell carcinoma (the deletion sate is 77.5%). The frequency of GST mu gene was not associated with smoking in both groups, but the higher deficiency rate was found in the low age group of lung cancer patients, showed 85.3% compared to the high age group, 68.1%. All the results showed that GST mu gene deletion may be an important host hereditary marker for susceptibility to lung cancer.
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PMID:[The study of GST mu gene deletion as the hereditary marker for susceptibility to lung cancer]. 856 87

We investigated whether lung cancer was associated with an increased micronucleus (MN) frequency in lymphocytes in a case-control study. Epidemiological data were obtained by an interviewer-administered questionnaire and included information on smoking history, intake of dietary micronutrients, general medical history, environmental and occupational exposures to mutagens and carcinogens, and family history of cancer. A modified cytokinesis-block method was used to determine individual MN frequency. Polymorphisms in glutathione S-transferase class mu were determined by PCR analysis. Overall, 55 controls and 42 cases were studied. MN frequency in cases and controls was not associated with age, smoking, metabolic genetic polymorphisms, environmental and occupational exposures, or medical history. Female controls had a significantly higher MN frequency than male controls (p = 0.05). Overall, MN frequency was significantly higher in cases than in controls (p < 0.01). Twenty-four cases (57%) had an MN frequency higher than the upper 95% confidence interval of the mean value for controls (11.5 MNs/1000 binucleated cells). Further analysis showed that, cases who were current and former smokers had significantly higher MN frequencies than controls (p = 0.04); this difference was not seen in the group that had never smoked. The significantly higher MN frequency among cases with a history of smoking may be attributable to the presence of lung neoplasm per se or to the interaction of smoking with endogenous factors associated with the development of lung cancer.
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PMID:Increased micronucleus frequency in lymphocytes from smokers with lung cancer. 856 91

CYP1A1 is responsible for the metabolic activation of benzo(a)pyrene in cigarette smoke, and high susceptibility to smoking-related lung cancer has been associated with the MspI polymorphism of the CYP1A1 gene. Individuals with a susceptible CYP1A1 genotype have been found to be at remarkably high risk when the genotype is combined with a deficient Mu-class glutathione S-transferase (GSTM1) genotype. In this study, we investigated the relationship between germ line polymorphisms of these genes and clinical characteristics or survival rates in 232 patients with non-small cell lung cancer (NSCLC). Statistical analysis revealed a significant association (P < 0.05) of the MspI polymorphism of the CYP1A1 gene with histological type, performance status (general conditions of patients), and the extent of the primary tumor (T-factor). On the other hand, the GSTM1 polymorphism was significantly associated with performance status, the extent of regional lymph node metastasis (N-factor), and the extent of distant metastasis (M-factor). NSCLC patients with at least one susceptible allele of the MspI polymorphism of the CYP1A1 gene [heterozygous genotype B or a rare homozygous genotype C; n = 131; median survival time (MST) = 24.2 months] were associated with a shortened survival compared with those with nonsusceptible homozygous alleles (genotype A; n = 101; MST = 65.2 months; P = 0.005 by log-rank test). Smokers with susceptible genotypes (n = 104; MST = 18.2 months) were markedly associated with a shortened survival compared with those with genotype A (n = 76; MST = 69.2 months; P = 0.024); such an association was not found among nonsmokers by genotypes. Genotype-dependent survival was also observed in patients at an advanced stage of disease (P = 0.010), but not in those at an early stage of disease (P = 0.382). Patients with the susceptible CYP1A1 genotype had remarkably shortened survivals when the genotype was combined with a deficient genotype GSTM1(-) (P = 0.017; degree of freedom = 3). Multivariate analysis by the Cox proportional hazards model also revealed that the CYP1A1 polymorphism was an independent prognostic factor in patients at a nonresectable advanced stage of NSCLC (P = 0.005; hazard ratio = 1.98; 95% confidence interval, 1.24-3.17).
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PMID:Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer. 870 15

Auto-antibodies against L-myc oncogene products (L-Myc) in sera from lung cancer patients were examined using bacterially synthesized glutathione S-transferase (GST) L-Myc fusion proteins and Western blot analysis. The detection rate of anti-L-Myc antibodies in sera from lung cancer patients was 10%, while that in sera obtained from normal volunteers was 0%. Five patients with non-small-cell lung cancers (2 adenocarcinomas, 2 squamous-cell carcinomas and I large-cell carcinoma) were included in the group with anti-L-Myc antibodies. These auto-antibodies belonged to the IgG class and recognized the carboxy terminus of L-Myc. Circulating L-Myc was not detected in sera from patients with anti-L-Myc antibodies. Differences in age, sex, performance status, histology, stage, smoking history and prior treatment were not significantly different between anti-L-Myc antibody-positive and antibody-negative patients. Anti-nuclear antibodies were detected in 40% of lung cancer patients and 57% of those with anti-L-Myc antibodies. Our data suggest that detection of anti-L-Myc antibodies may be helpful in the diagnosis and evaluation of the host-immune response to L-Myc in a subset of lung cancer patients.
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PMID:Detection of auto-antibodies against L-myc oncogene products in sera from lung cancer patients. 879 69

Most of chemical carcinogens require metabolic activation before they interact with cellular macromolecules and can cause cancer initiation. Many of cytochrome P-450 (CYP) mediating oxidative enzymes and conjugation enzymes, cloned and characterized in humans, show genetic and phenotypic polymorphisms and have been suggested to contribute to individual cancer susceptibility as genetic modifiers of cancer risk. Altered phenotypes and genotypes in CYP1A1, CYP2D6 and CYP2E1 and in defective glutathione S-transferase (GST) and N-acetyltransferase enzymes have been associated with an increased risk of developing lung and other cancers. The risk to lung cancer is dramatically increased in the population carried simultaneously high-risk genotypes in CYP1A1 and GSTM1. There are, however, several studies in each category in which no association have been found.
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PMID:[Genetic and phenotypic polymorphisms in carcinogen-metabolizing enzymes and cancer susceptibility]. 881 Aug 6

Tobacco is responsible for 80 to 90% lung cancer cases in industrialized countries. However, genetic factors are likely to be involved in lung cancer susceptibility. Some degree of familial aggregation of lung cancer is evidenced in most family studies. On the other hand, many tobacco carcinogens are metabolised by enzymes of the P450 cytochrome family. Two enzymes of cytochrome P450, CYP1A1 and CYP1A2, are inducible by tobacco carcinogens, and animal studies evidenced a genetic polymorphism of CYP1A1 associated with tumour occurrence after administration of a polycyclic aromatic hydrocarbon. In humans, an association between lung cancer and some P450 polymorphisms (CYP1A1, CYP2D6, CYP2E1) was suggested but the results of epidemiologic studies are discordant and difficult to interpret. In addition, there is a polymorphism of glutathione S-transferase isoenzyme (GSTM1) involved in carcinogen elimination; an association between this polymorphism and lung cancer has also been reported. Further studies on combined effects of these polymorphisms should allow an identification of sub-groups of individuals at high risk of lung cancer.
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PMID:[Susceptibility to bronchial cancer: an example of genetic-environmental interaction]. 883 May 63

Lung cancer has been associated with smoking and many carcinogenic compounds are thought to contribute to the origin of lung cancer. Most of these carcinogens exert their carcinogenicity after conversion to more potent forms through reactions mediated by drug-metabolizing enzymes, such as cytochrome P450s (CYPs). Carcinogens in the human body are then detoxified by enzymes such as glutathione S-transferase (GST) and excreted. The genetic differences, or polymorphisms, of these enzymes may affect genetically-determined susceptibility to lung cancer. Recently, a variety of polymorphisms have been found for drug-metabolizing enzymes in humans, such as CYP2E1, CYP1A1, CYP2D6, and GST. These polymorphisms have been related to susceptibility to lung cancer by some researchers. Their relevance with the dose of tobacco smoke has also been investigated.
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PMID:[Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to lung cancer--relevance to smoking]. 883 7

We examined the effect of selective thromboxane A2 (TXA2) receptor antagonists, calcium 5(Z)-1R, 2S, 3S, 4S-7-[3-phenylsulphonylaminobicyclo [2.2.1] hept-2-yl]-5-heptonoate hydrate (S-1452) and +/- -7-(3,5,6,-trimethyl-1,4-benzoquinon-2-yl)-7-phenylhaptanoic acid (AA-2414), on sensitivity to cis-diamminedichloroplatinum (II) (CDDP) in non-small-cell lung cancer cell lines. IC50 values to CDDP using MTT assay were decreased 2.1- and 4.6-fold respectively by treatment with 250 or 500 microM S-1452, for a 2 h simultaneous drug exposure, and those of PC-9/CDDP, a CDDP-resistant cell line, were decreased 3.1- and 6.1-fold. Sensitivity to carboplatin was also enhanced by the treatment with S-1452. IC50 values to CDDP and carboplatin were decreased by treatment with AA-2414 in a dose-dependent manner. Isobologram analysis showed that the combination of CDDP with S-1452 or AA-2414 produced supra-additive or additive effects in each cell line. Neither glutathione content nor glutathione S-transferase activity was changed in either cell line by treatment with 500 microM S-1452. Accumulation of platinum into PC-9 and PC-9/CDDP was increased by the treatment in a dose-dependent manner. Na+, K+-ATPase activity of PC-9 and PC-9/CDDP was enhanced by the treatment of S-1452 in a dose-dependent manner. These data show that the TXA2 receptor antagonists may enhance the sensitivity of non-small-cell lung cancer cell lines to platinum agents. Increase in Na+, K+-ATPase activity induced by S-1452 may be the mechanism of its sensitising effect through increase in platinum accumulation.
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PMID:Modulation of sensitivity to cis-diamminedichloroplatinum (II) by thromboxane A2 receptor antagonists in non-small-cell lung cancer cell lines. 893 34

In addition to being a potent hepatocarcinogen, aflatoxin B1 (AFB1) is a pulmonary carcinogen in experimental animals, and epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. This study investigated AFB1 bioactivation and detoxification in human lung tissue obtained from patients undergoing clinically indicated lobectomy. [3H]AFB1 was bioactivated to a DNA binding metabolite by human whole lung cytosols in a time-, protein concentration-, and AFB1 concentration-dependent manner. Cytosolic activation of [3H]AFB1 correlated with lipoxygenase (LOX) activity and was inhibited by the LOX inhibitor nordihydroguaiaretic acid (NDGA; 100 microM), indicating that LOXs were largely responsible for the observed cytosolic activation of AFB1. In whole lung microsomes, low levels of indomethacin inhibitable prostaglandin H synthase (PHS)-mediated [3H]AFB1-DNA binding and cytochrome P-450 (P450)-mediated [3H]AFB1-DNA binding were observed. Cytosolic glutathione S-transferase (GST)-catalyzed detoxification of AFB1-8,9-epoxide, produced by rabbit liver microsomes, was minimal at 1 and 10 microM [3H]AFB1. With 100 microM [3H]AFB1, [3H]AFB1-8,9-epoxide conjugation with reduced glutathione was 0.34 +/- 0.26 pmol/mg/h (n = 10). In intact, isolated human lung cells, [3H]AFB1 binding to cellular DNA was higher in cell fractions enriched in macrophages than in either type II cell-enriched fractions or fractions containing unseparated cell types. Indomethacin produced a 63-100% decrease in [3H]AFB1-DNA binding in macrophages from five of seven patients, while NDGA inhibited [3H]AFB1-DNA adduct formation by 19, 40 and 56% in macrophages from three of seven patients. In alveolar type II cells, NDGA decreased [3H]AFB1-DNA binding by 30-100% in cells from three patients and indomethacin had little effect. SKF525A, an isozyme non-selective P450 inhibitor, enhanced [3H]AFB1 binding to cellular DNA in unseparated cells, macrophages, and type II cells, suggesting that P450-mediated bioactivation of AFB1 is not a major pathway by which AFB1-8,9-epoxide is formed in human lung cells. Overall, these studies suggest that P450 has a minor role in the bioactivation of AFB1 in human lung. Rather, LOXs and PHS appear to be important bioactivation enzymes. Co-oxidative bioactivation of AFB1, in combination with the low conjugating activity displayed by human lung cytosolic GSTs, likely contributes to human pulmonary susceptibility to AFB1.
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PMID:Biotransformation of aflatoxin B1 in human lung. 896 67


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