Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Twenty tumoral and peritumoral tissues from patients with lung cancer were analyzed immunohistochemically for the drug resistance-related proteins P-glycoprotein (P-170), topoisomerase II (Topo-II), glutathione S-transferase-pi (GST-pi), metallothionein (MT), heat shock protein-70 (HSP-70) and the putative regulators of resistance (ErbB1, Fos and Jun). Protein expression of Topo-II, GST-pi, MT, HSP-70, ErbB1, Fos and Jun was elevated in tumor tissue in comparison to normal tissue. The different expression of the proteins between tumoral and normal tissues was statistically significant for Topo-II (P = 0.05), MT (P = 0.03), and HSP-70 (P = 0.01), whereas ErbB1 showed a borderline significance. The expression of the proteins was frequently increased in smokers in comparison to non-smokers. In general, the increase of the proteins of smokers corresponded in tumoral and non-tumoral tissue. Different expression was only found with MT and HSP-70 which were higher in tissues of smokers.
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PMID:Expression of resistance-related proteins in tumoral and peritumoral tissues of patients with lung cancer. 901 91

Increased lung cancer risk associated with genetic polymorphism of glutathione S-transferase (GST, EC 2.5.1.18) isozyme mu was examined in a Chinese population. A significantly higher proportion in lung cancer patients showed GST mu deficiency compared with control group (71.0% vs. 51.1%, P < 0.005). Although the susceptibility to lung cancer showing gene deletion for GST mu isoform in non-smoking group is not significantly different from that in smoking group, a great number of individuals with gene deletion was found among cancer patients who are less than 50 years old. The pathology of lung tumors related to that lack of class mu isoform which occurred most frequently in patients with small cell carcinomas. Thus, present data further support that sensitivity to chemical toxins and pulmonary carcinogens may be affected by GST mu isoform polymorphism.
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PMID:Gene deficiency of glutathione S-transferase mu isoform associated with susceptibility to lung cancer in a Chinese population. 906 18

Two variant glutathione S-transferase cDNAs have been described at the GSTP1 locus, which differ by a single base pair (A-G) substitution at nucleotide 313 of the GSTP1 cDNA. This results in an amino acid substitution which alters the function of the enzyme. In this study, a novel PCR assay has been developed which demonstrates that these two variant cDNAs represent distinct GSTP1 alleles (GSTP1a and GSTP1b). In a study of individuals with different forms of cancer, the GSTP1b allele is found to be strongly associated with bladder cancer and testicular cancer. In controls 6.5% of individuals were homozygous for the GSTP1b allele. In bladder cancer cases, this rose to 19.7% [n = 71, odds ratio 3.6 (1.4-9.2), P = 0.006] and in testicular cancer to 18.7% [n = 155, odds ratio 3.3 (1.5-7.7), P = 0.002]. In addition, in prostate cancer a highly significant decrease in the frequency of the GSTP1a homozygotes was observed [control 51.0% versus 27.8% cancer cases, n = 36, odds ratio 0.4 (0.02-3.3), P = 0.008]. Increases in the frequency of GSTP1b homozygotes was also observed in lung cancer and chronic obstructive pulmonary disease. However, these were not statistically significant. No change in breast or colon cancer allele frequencies was observed.
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PMID:Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer. 911 Nov 93

Cross-resistance presents an obstacle in cancer chemotherapy. Cadmium is a potential carcinogen whose exposure has been shown in epidemiological and laboratory experiments to cause lung cancer. Cadmium also induces various forms of resistance in human lung carcinoma cells. This resistance may be shared by antineoplastic agents, which should be a concern for chemotherapy of cadmium-induced lung cancer. In the present study, two subpopulations of human lung carcinoma A549 cells with a different magnitude of resistance to cadmium toxicity were shown to have a parallel resistance to the cytotoxic action of Adriamycin (ADR), an important anticancer drug. Several factors were examined to investigate the mechanism(s) for the cross-resistance, including cellular metallothionein and glutathione (GSH) concentrations, glutathione S-transferase activity, mdr1 expression, and antioxidant enzyme activities including superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Only cellular GSH content was elevated consistently in the cadmium/ADR-resistant cells relative to the cadmium/ADR-sensitive cells. Treatment with buthionine sulfoximine, a specific inhibitor of GSH synthesis sensitized both cell lines to ADR only when the cellular GSH levels were depleted to about 5% of control. This BSO treatment, however, did not affect cell viability. Further study revealed that the cadmium/ADR-resistant cells have a greater capacity in recovery of cellular GSH content following BSO treatment. The results demonstrate that cross-resistance to ADR exists in cadmium-resistant human lung carcinoma A549 cells, and enhanced GSH synthesis capacity, rather than elevated levels of cellular GSH, may be related to this resistance.
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PMID:Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells. 911 95

Epidemiological studies have led to the suggestion that a genetic basis may exist in the individual variation in predisposition to cancer. Interindividual differences in human toxicological response to carcinogenic exposure have been attributed to heritable polymorphisms in metabolism, namely glutathione S-transferases (GSTs) coding for enzymes that are known to be detoxifiers of carcinogens. Within the human GST mu class, there is a specific isozyme that is frequently lacking. To check whether or not this association exists in the Portuguese population with lung cancer, we used polymerase chain reaction (PCR)-based genotyping to examine GSTM1 polymorphism (nulled and non-nulled) in 84 individuals as a control healthy population and a group of 98 lung cancer patients. In this study we were able to find a frequency of the GSTM1 phenotype among our healthy control subjects consistent with earlier genotyping studies in other Caucasoid populations. For the group of individuals with lung cancer as a whole, or in subsets of histological subtypes, our data for the Portuguese population did not show a positive correlation between the null allele and this neoplasm. In contrast, we found a slight increase in the frequency of the wild-type allele in our lung cancer group.
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PMID:Glutathione S-transferase mu polymorphism and susceptibility to lung cancer in the Portuguese population. 912 92

We evaluated the effects of a panel of glutathione derivative (S-butyl, S-decyl, S-ethyl, S-heptyl, S-hexyl; S-methyl, S-nonyl, S-octyl, S-propyl and S-pentyl glutathiones) on glutathione-S-transferase activity in the cell lysates of a human lung cancer, PC-9. Glutathione derivatives inhibited glutathione-S-transferase activity in PC-9 cell lysates by up to 67%. When PC-9 cells were incubated with the IC50 concentration of adriamycin (200 nM) and with nontoxic concentrations (1 microM) of the glutathione derivatives, cytotoxicity ranged from -20% to +55% of the control levels. Enhancement of adriamycin toxicity by glutathione derivatives was significantly correlated with the inhibition of glutathione-S-transferase activity. S-decyl-glutathione, which was one of the most potent inhibitors of glutathione-S-transferase activity, significantly enhanced the adriamycin-induced antitumor effect in vivo. Findings suggest that some glutathione derivatives, including the S-decyl, S-octyl, and S-hexyl glutathiones, enhance adriamycin-induced cytotoxicity in part by inhibiting glutathione-S-transferase and that these agents may be useful as chemosensitizers for adriamycin therapy. In conclusion, the present results showed that some glutathione derivatives enhanced sensitivity of tumor cells to ADR by inhibiting GST activity. The use of BSO and EA as sensitizers to chemotherapy is currently being evaluated in clinical trials. The present data suggest that the use of GSH derivatives to modulate GST activity may improve the response to ADR.
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PMID:Glutathione derivatives enhance adriamycin cytotoxicity in a human lung adenocarcinoma cell line. 921 76

The A-G polymorphism at codon 104 in the glutathione S-transferase P1 (GSTP1) gene was examined in 138 male lung cancer patients and 297 healthy controls. The patients had significantly higher frequency of the GG genotype (15.9%) and a lower frequency of AA (38.4%) than the controls (9.1% and 51.5%, respectively). The level of hydrophobic DNA-adducts were determined in lung tissue from 70 current smokers. Patients with the GG genotype had a significantly higher adduct level than patients with AA (15.5 +/- 10.2 vs 7.9 +/- 5.1 per 10(8) nucleotides, P = 0.006). We also analyzed the deletion polymorphism in the GSTM1 gene in 135 male patients and 342 controls. The patients were stratified according to histology, smoking dose, age, adduct level and mutational types found in the tumors (Ki-ras and p53 genes). The results consistently indicated that the GSTM1 null genotype was associated with a slightly increased lung cancer risk. When the combined GST M1 and P1 genotypes were examined, patients with the combination null and AG or GG had significantly higher adduct levels than all other genotype combinations (P = 0.011). The distribution of combined genotypes was also significantly different in cases and controls, mainly due to increased frequency of the combination GSTM1 null and GSTP1 AG or GG among patients.
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PMID:Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk. 923 Feb 69

Gene deletion at the glutathione S-transferase mu locus (GSTM1) has previously been associated with increased risk for environmentally-induced cancers (e.g. smoking-related lung cancer). In the present study we examined the hypothesis that GSTM1 deletion is a risk factor for malignant brain tumors in adults. We compared the prevalence of the GSTM1 homozygous deletion polymorphism in 158 Caucasian adults with gliomas with 157 controls. Cases and controls were drawn from a large population-based case-control study of brain cancers in six San Francisco Bay area counties. Overall, the prevalence of the GSTM1 deletion was similar in cases (83/158; 53%) and controls (78/157; 50%). Among brain tumor cases, analysis of variance modeling indicated a significant interaction of GSTM1 genotype and gender associated with age at diagnosis (P = 0.02). This effect was due to the fact that women with GSTM1 deletion were younger on average at diagnosis than women who were GSTM1 positive (43.9 years versus 52.4 years, respectively). Age at diagnosis among men was similar for those who were GSTM1 deleted and GSTM1 positive (49.4 years and 47.2 years, respectively). The younger age at diagnosis of GSTM1 null female cases compared with GSTM1 positive cases was observed in astrocytoma as well as the higher grade tumors (e.g. glioblastoma multiforme). There was no association of GSTM1 deletion with age or gender in controls. These studies suggest that among female cases, GSTM1 deletion may be associated with earlier age at onset. Confirmation of these findings could provide important clues to gene-environment interactions in the etiology of malignant brain tumors.
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PMID:Population-based study of glutathione S-transferase mu gene deletion in adult glioma cases and controls. 923 Feb 93

The genes coding for separate isoforms of both the human glutathione S-transferase class mu and class theta enzymes (GSTM1 and GSTT1) are polymorphic with a variable ethnic distribution. These enzymes detoxify reactive epoxides, including carcinogens produced by tobacco smoke. Because of this, the null polymorphism in the GSTM1 gene (coding for the glutathione S-transferase class mu enzyme) has been studied widely as a possible source of inherited susceptibility to smoking-related lung cancer. The more recently described null polymorphism in the GSTT1 gene also could contribute to an increased risk of smoking-related lung cancer. As the incidence of lung cancer is known to differ by ethnicity, we have conducted a case-control study in the United States of 108 African-Americans (Blacks) and 60 Mexican-Americans (Hispanics) with lung cancer and 132 African-American (Black) and 146 Mexican-American (Hispanic) controls to investigate the association of the GSTT1 and GSTM1 polymorphisms with lung cancer in minority populations. In the unadjusted data, there was a borderline significant association of the GSTM1 null polymorphism with lung cancer in Mexican-Americans (odds ratio [OR] = 1.8, 95 percent confidence interval [CI] = 1.0-3.3 ) that was not observed in African-Americans. The GSTT1 null polymorphism also had a higher prevalence in cases than controls in both racial/ethnic groups, but this increase was not statistically significant. When the data were analyzed using logistic regression controlling for age, gender, race, and smoking, no significant association of either trait with lung cancer was observed, with ORs for both traits of approximately 1.3. However, when the prevalence of individuals who were null for both polymorphisms was compared by case status, a significant interaction was observed. Logistic regression models showed the OR for the association of lung cancer and the presence of both null polymorphisms compared with one (either GSTT1 or GSTM1) or no null genotype to be 2.9 (P < 0.04). These results suggest that there may be carcinogenic intermediates in cigarette smoke that are substrates for both the GSTT1 and GSTM1 enzymes, and that lung cancer risk is increased more than additively for individuals who have both GSTT1 and GSTM1 null polymorphisms.
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PMID:Polymorphisms in the glutathione S-transferase class mu and theta genes interact and increase susceptibility to lung cancer in minority populations (Texas, United States). 924 70

Increased risk of environmentally induced cancer is associated with various types of exposures and host factors, including differences in carcinogen metabolism. Since many carcinogenic compounds require metabolic activation to enable them to react with cellular macromolecules, individual features of carcinogen metabolism may play an essential role in the development of environmental cancer. In this context, cigarette smoking has often been the main type of carcinogenic exposure examined in human studies. Increasing attention has recently been paid to the dose level at which individual susceptibility may be observed. Present studies on increased risk of smoking-related lung cancer associated with phenotypic or genotypic variation of the genes encoding for CYP1A1 or CYP2D6 enzymes are summarized. Similarly, higher risks of lung or bladder cancer seen at various levels of smoking in association with polymorphism of the glutathione S-transferase gene GSTM1 or NAT1 and NAT2 genes involved in N-acetylation are reviewed. Finally, the influence of CYP2E1, GSTM1, or the combined at-risk genotype on the risk of hepatocellular carcinoma in smokers is briefly discussed.
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PMID:Interaction between dose and susceptibility to environmental cancer: a short review. 925 56


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