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 GSTM1 (glutathione S-transferase mu-1) null genotype is suspected of increasing an individual's susceptibility to tobacco smoke carcinogens because of impaired carcinogen detoxification. We were interested in whether there were differences in lung cancer susceptibility to smoking within the GSTM1 genotypes and the impact of antioxidant supplementation on this. For this purpose, we conducted a nested lung cancer case-control study and evaluated the role of GSTM1 within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. GSTM1 genotype status was determined for 319 cases and 333 controls using a PCR-based approach. GSTM1 was evaluated as an independent risk factor and as an effect modifier of smoking using logistic regression analyses. The GSTM1 null genotype itself was unrelated to risk of lung cancer, odds ratio (OR) = 1.09 and 95% confidence interval (CI), 0.79-1.50, but it may have modified the effect of smoking. There was a suggestion for a stronger association between years of smoking and lung cancer among the GSTM1 null genotype, but the differences between GSTM1 null and present genotypes were not statistically significant (P = 0.12). Furthermore, the smoking association was strongest among those with the GSTM1 null genotype not receiving alpha-tocopherol supplementation, whereas among those receiving alpha-tocopherol, there was no modification by GSTM1 on the association between smoking duration and lung cancer risk. Beta-carotene supplementation did not modify the relationship between GSTM1, smoking years, and lung cancer risk. In conclusion, GSTM1 is not associated with lung cancer risk in male smokers but may confer a higher susceptibility to cumulative tobacco exposure. This association may be attenuated by alpha-tocopherol but not by beta-carotene supplementation.
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PMID:Effect of vitamin intervention on the relationship between GSTM1, smoking, and lung cancer risk among male smokers. 1056 50

Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.
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PMID:Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers. 1057 54

Several studies have documented that induction of the glucose-related protein (GRP78) is associated with the development of drug-resistance to antitumor drugs. However, nothing has been reported concerning GRP78 in human lung tumors and its relationship to several resistance proteins and angiogenesis. Therefore, this study analyzed the expression of GRP78 in a series of 62 consecutive lung cancer patients and examined whether or not a relationship exists between GRP78, several resistance proteins and microvessel density (MVD). Secondary, it evaluated the relationship of GRP78, LRP56 and GST-pi in cancer cell lines under hypoxic conditions and in sensitive and resistant cell lines. We determined that a relationship exists between GRP78 and the resistance proteins P170, LRP56 and GST-pi in human lung cancer. Furthermore, we observed an up-regulation of GRP78 in the resistant cell lines LUTC-ML54, OAW-Dox and OAW-Tax, but not in sensitive cell lines. Abnormal vascularization of malignant tumors is associated with the development of hypoxic regions. In hypoxic regions, several proteins, including drug resistance proteins, are expressed in greater quantities. Our study detected an inverse correlation between GRP78 and MVD. Carcinomas with low MVD exhibited a higher expression of GRP78. Furthermore, protein expression of GRP78, GST-pi and LRP56 increased in the cell lines A-549, RPMI-2650 and SC-MES-1 under hypoxic conditions. These observations suggest that hypoxia, tumor vascularization and the simultaneous expression of many resistance-related proteins, including GRP78, may play an important role in drug response and therapeutic effectiveness.
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PMID:Glucose-related protein (GRP78) and its relationship to the drug-resistance proteins P170, GST-pi, LRP56 and angiogenesis in non-small cell lung carcinomas. 1062 96

Molecular epidemiology of lung cancer analyses relationship between environment and individual susceptibility. Studying biomarkers of risk at the molecular level allows better understanding of chemical carcinogenesis processes and makes possible early detection of the disease as well as helps its prevention. Risk biomarkers include genetic polymorphism of CYP, GST and NAT genes that participate in metabolic biotransformation of various endo- and exogenous compounds including carcinogens. Exposure to potentially carcinogenic environmental factors plays an important role in etiology of lung cancer, which remains a leading cause of cancer death worldwide. This review presents current knowledge about molecular basis and impact of individual variations in carcinogen metabolism on lung cancer risk.
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PMID:[Individual predisposition to lung neoplasm--the role of genes involved in metabolism of carcinogens]. 1064 42

The heterogeneous nuclear ribonucleoproteins (hnRNP) associate with pre-mRNA in the nucleus and play an important role in RNA processing and splice site selection. In addition, hnRNP A proteins function in the export of mRNA to the cytoplasm. Although the hnRNP A proteins are predominantly nuclear, hnRNP A1 shuttles rapidly between the nucleus and the cytoplasm. HnRNP A2, whose cytoplasmic overexpression has been identified as an early biomarker of lung cancer, has been less well studied. Cytosolic hnRNP A2 overexpression has also been noted in brain tumors, in which it has been correlated with translational repression of Glucose Transporter-1 expression. We now examine the role of arginine methylation on the nucleocytoplasmic localization of hnRNP A2 in the HEK-293 and NIH-3T3 mammalian cell lines. Treatment of either cell line with the methyltransferase inhibitor adenosine dialdehyde dramatically shifts hnRNP A2 localization from the nuclear to the cytoplasmic compartment, as shown both by immunoblotting and by immunocytochemistry. In vitro radiolabeling with [(3)H]AdoMet of GST-tagged hnRNP A2 RGG mutants, using recombinant protein arginine methyltransferase (PRMT1), shows (i) that hnRNP A2 is a substrate for PRMT1 and (ii) that methylated residues are found only in the RGG domain. Deletion of the RGG domain (R191-G253) of hnRNP A2 results in a cytoplasmic localization phenotype, detected both by immunoblotting and by immunocytochemistry. These studies indicate that the RGG domain of hnRNP A2 contains sequences critical for cellular localization of the protein. The data suggest that hnRNP A2 may contain a novel nuclear localization sequence, regulated by arginine methylation, that lies in the R191-G253 region and may function independently of the M9 transportin-1-binding region in hnRNP A2.
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PMID:The RGG domain in hnRNP A2 affects subcellular localization. 1077 24

We examined the association between the gene expression levels of glutathione S-transferase-pi (GST-pi) and platinum drug exposure in human lung cancer. First we monitored GST-pi gene expression levels in two lung cancer cell lines and in peripheral mononuclear cells of ten previously untreated lung cancer patients after platinum drug exposure. Next we examined GST-pi gene expression levels in 40 lung cancer autopsy specimens. The GST-pi gene expression levels were assessed by the quantitative reverse transcription-polymerase chain reaction or Northern blot analysis. The GST-pi gene expression was not induced by platinum drugs either in vitro and in vivo within 24 h of exposure. In contrast, GST-pi gene expression levels in lung cancer tissues of patients who had been exposed to platinum drugs at least 1 month before death were significantly higher than that in those of patients who had not been exposed. These results suggest that GST-pi gene expression is associated with chronic exposure to platinum drugs in lung cancer and/or the stress response to xenobiotics.
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PMID:Glutathione S-transferase-pi gene expression and platinum drug exposure in human lung cancer. 1084 Jan 64

The lung cancer mortality rate in Xuan Wei County, China is among the highest in the country and has been associated with exposure to indoor smoky coal emissions that contain high levels of polycyclic aromatic hydrocarbons. This risk may be modified by variation in metabolism genes, including GSTM1, which encodes an enzyme known to detoxify polycyclic aromatic hydrocarbons. To investigate the relationship between GST genotypes and lung cancer risk in Xuan Wei County, we analyzed GSTM1 and GSTT1 genotypes in a population-based case-control study. A total of 122 lung cancer patients and 122 controls, individually matched by age, sex, and home fuel type, were studied. Compared to subjects who used less than 130 tons of smoky coal during their lifetime, heavier users (> or =130 tons) had a 2.4-fold (95% confidence interval, 1.3-4.4) increased risk of lung cancer. The GSTM1-null genotype was associated with a 2.3-fold (95% confidence interval, 1.3-4.2) increased risk of lung cancer. Furthermore, there was some evidence that smoky coal use was more strongly associated with lung cancer risk among GSTM1-null versus GSTM1-positive individuals. In contrast, the GSTT1 genotype was not significantly associated with lung cancer risk. Our data suggest that the GSTM1-null genotype may enhance susceptibility to air pollution from indoor coal combustion emissions.
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PMID:Indoor coal combustion emissions, GSTM1 and GSTT1 genotypes, and lung cancer risk: a case-control study in Xuan Wei, China. 1086 96

The human glutathione S-transferase (GST) P1 alleles coding for Val(105) (hGSTP1*B and/or P1*C) are over- represented in lung cancer patients. However, the corresponding recombinant Val(105) protein variants tend to show higher catalytic activity than the Ile(105) variants towards bay-region diol epoxides that are thought to be etiological agents in lung cancer. We have examined 29 normal human lung samples with respect to several factors that could confound relationships between hGSTP1 allele type and cancer susceptibility, namely, inter-individual and allele-specific variation of hGSTP1 expression, and differences between the catalytic properties of the native and recombinant hGSTP1-1 variant protein products. hGSTP1 expression varied 7-fold among individuals but was independent of hGSTP1*A, P1*B or P1*C allele type. hGST subunits A1, A2, M1 and M3 were minor components, similarly variable in expression. Despite this variability of expression, the levels of hGSTP1 expression linearly correlated with those of the next most highly expressed GST, hGSTM3, even though the genes for these GSTs are on different chromosomes. Differences between the native protein variants, using 1-chloro-2,4-dinitrobenzene and (+)-anti-benzo[a]pyrene diolepoxide as substrates, were more marked than those between the recombinant variants. However, the order of differential catalytic specificity was the same for native and recombinant variants. Neither the expression of the hGSTP1 alleles nor the catalytic properties of the protein variants appears to provide a simple mechanistic rationale for the observed over-representation of the hGSTP1*B and/or 1*C alleles in lung cancer.
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PMID:Expression of hGSTP1 alleles in human lung and catalytic activity of the native protein variants towards 1-chloro-2,4-dinitrobenzene, 4-vinylpyridine and (+)-anti benzo[a]pyrene-7,8-diol-9,10-oxide. 1088 Jul 66

Patients with unresectable non-small-cell lung cancer (NSCLC) usually have undergone chemotherapy; however, such problems as resistance to chemotherapeutic agents occur during the treatments. Recent studies have indicated that glutathione S-transferase-pi (GST-pi) may play an important role in the resistance of cancer cells to alkylating agents, including cisplatin compounds. We examined a possible relationship between immunohistochemical expression of GST-pi and the response to cisplatin plus etoposide chemotherapy in patients with untreated and unresectable primary NSCLC. Of the 89 patients, 50 (56.2%) were GST-pi-positive and 39 (43.8%) were GST-pi-negative. For the patients with negative GST-pi expression, the response rate was 66.7% (26 of 39 patients). In the patients with positive GST-pi expression, the response rate was 26% (13 of 50 patients). This difference was statistically significant (P = .0019). The results suggest that GST-pi expression in NSCLC tissues is related to response to cisplatin plus etoposide chemotherapy and may be useful as a predictor of chemotherapy response.
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PMID:Immunohistochemical expression of glutathione transferase-pi in untreated primary non-small-cell lung cancer. 1097 87

The glutathione S-transferases (GSTs) are widely expressed in mammalian tissues and involved in Phase II detoxification reactions. The GSTs form a supergene family consisting of four distinct families, named alpha (GSTA), mu (GSTM) theta (GSTT) and pi (GSTP). Several of the GST genes are polymorphic in humans and are currently being investigated as possible cancer-risk modifiers. Among the GST genes, we examined GSTP1 polymorphism in exon 5 among male lung cancer patients (n = 86, male Japanese) and male healthy controls (n = 80, male Japanese) by restriction fragment length polymorphism-polymerase chain reaction method. The cancer patients showed frequency of the GSTP1 mutated genotype (individuals having at least one mutant allele, 29.1%) very similar to that of the control subjects (28.8%). After adjusting for smoking status, no association was found between the GSTP1 mutated genotype and lung cancer risk (odds ratio: 0.95; 95% confidence interval: 0.48-1.90). When study subjects were divided into two subgroups based on smoking status, the GSTP1 mutated genotype was not associated with an increased risk of lung cancer among smokers and non-smokers. These results suggest that GSTP1 polymorphism in exon 5 alone may not increase the risk of lung cancer in male Japanese.
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PMID:[Lung cancer risk and genetic polymorphism at the glutathione S-transferase P1 locus in male Japanese]. 1100 66


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