Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke may cause human lung cancer via metabolic activation to ultimate carcinogens. p53 is one of the most commonly mutated tumor suppressor genes in this disease. An analysis of the p53 mutational database shows that G to T transversions are a signature mutation of lung cancer. Aldo-keto reductases (AKRs) activate PAH trans-dihydrodiol proximate carcinogens to yield their corresponding reactive and redox-active o-quinones, e.g., benzo[a]pyrene-7,8-dione (BP-7,8-dione). We employed a yeast reporter system to determine whether PAH o-quinones or the ROS they generate cause change-in-function mutations in p53. N-Methyl-N-nitroso-N'-nitro-guanidine, a standard alkylating mutagen was used as a positive control. MNNG caused a dose-dependent increase in mutant yeast colonies and at the highest concentrations 8-14% of the yeast colonies were mutated and were characterized by G:C to A:T transitions in the p53 DNA binding domain. Treatment of p53 cDNA with micromolar concentrations of (+/-)-anti-7,8-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene, (anti-BPDE, an ultimate carcinogen) or sub-micromolar concentrations of BP-7,8-dione in the presence of redox-cycling conditions (NADPH and CuCl(2)) also caused p53 mutations in a dose-dependent manner. We found that no mutants were observed with PAH o-quinones or NADPH alone. p53 mutagenesis by BP-7,8-dione was attenuated by ROS scavengers and completely abrogated by a combination of superoxide dismutase and catalase, indicating that both superoxide anion and hydroxyl radicals were the responsible mutagens. The bulk of the mutations detected were single-point mutations and were not random in occurrence. Over 46% of BP-7,8-dione-induced mutations were G:C to T:A transversions, consistent with the formation of 8-oxo-dGuo or its secondary oxidation products. In addition, 25% of these mutations were at hotspots in p53 which are known to be mutated in lung cancer. Together these data suggest that PAH o-quinones generate an endogenous mutagen (ROS) which leads to p53 inactivation. These observations provide an alternative route to G to T transversions that dominate in p53 in lung cancer.
 ...
PMID:Reactive oxygen species generated by PAH o-quinones cause change-in-function mutations in p53. 1206 51

The dietary consumption of antioxidant-rich fruits and vegetables is inversely correlated with the incidence of various diseases like cardiovascular diseases and lung cancer. We have tried to find out how far the S-allyl cysteine sulfoxide (SACS) isolated from garlic (Allium Sativum L.) can combat the nicotine-induced peroxidative damage in rats. The effects have been compared with the standard antioxidant vitamin E. Administration of SACS or vitamin E (100 mg/kg) to nicotine (0.6 mg/kg) treated rats for 21 days showed decreased concentrations of thiobarbituric acid reactive substances, hydroperoxides, and conjugated dienes in liver, lungs, and heart as compared with the values found in rats treated with nicotine alone. The activities of catalase and superoxide dismutase increased. The levels of the antioxidants like vitamins A, C, and E in the liver and glutathione in all tissues increased significantly in SACS-treated or vitamin E fed rats. However, the antioxidant status was higher when vitamin E was administered as compared with SACS administered to nicotine-treated rats.
 ...
PMID:A comparative study of antioxidants S-allyl cysteine sulfoxide and vitamin E on the damages induced by nicotine in rats. 1257 5

The cytoprotective effect of piperine on benzo[a]pyrene (B[a]P) induced experimental lung cancer was investigated in male Swiss albino mice. Oral administration of piperine (100 mg/kg body wt.) effectively suppressed lung cancer initiated with B[a]P as revealed by the decrease in the extent of lipid peroxidation with concomitant increase in the activities of enzymatic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymatic antioxidant (reduced glutathione, vitamin E and vitamin C) levels when compared to lung cancer bearing animals. Our data suggest that piperine may extend its chemopreventive effect by modulating lipid peroxidation and augmenting antioxidant defense system.
 ...
PMID:Cytoprotective effect of piperine against benzo[a]pyrene induced lung cancer with reference to lipid peroxidation and antioxidant system in Swiss albino mice. 1262 2

The study covered 152 lung cancer patients and 210 controls. The results of the study indicated decreased selenium (Se) concentrations and lowered activity of erythrocyte antioxidant enzymes (glutathione peroxidase, superoxide dismutase, glutathione-S-transferase) in the blood of lung cancer patients, as well as significantly increased concentrations of vitamin E in erythrocytes and thiobarbituric acid reactive substances in the plasma of the study population. Low plasma Se concentrations (< 45.7 microg/L) enhance the estimated risk of lung cancer (odds ratio = 3.047, p < 0.001). A more precise exposure assessment is required to identify the association between lung cancer incidence and occupational exposure to carcinogens.
 ...
PMID:Oxidative-stress markers in blood of lung cancer patients occupationally exposed to carcinogens. 1266 45

We carried out an open, non-randomized phase II study including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or stable disease (SD). The treatment consisted of administration of recombinant interleukin-2 (rIL-2) at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month plus medroxyprogesterone acetate (MPA) 500 mg/day every other day plus antioxidant agents alpha-lipoic acid 300 mg/day and N-acetyl cysteine 1800 mg/day or carbocysteine lysine salt oral solution 2.7 g/day. The treatment was administered for 1 year except when progression of disease occurred. The primary study endpoints were to define clinical outcome, i.e. duration of response, survival (overall survival, OS and progression-free survival, PFS), the toxicity profile, and the evaluation of quality of life (QL). As secondary endpoints, we measured the changes of lymphocyte count, serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin, blood levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione peroxidase, GPx and superoxide dismertase, SOD). From July 1998 to June 2003, 42 patients were enrolled in the study (M/F ratio, 39/3; mean age, 62.5 years). Twenty (47.6%) patients were elderly (> 65 years). The majority of patients had either head and neck cancer or lung cancer, 88% had locally advanced or metastatic disease at diagnosis, and 76% had ECOG 0. Forty patients were previously treated with chemotherapy (27 also with radiotherapy), two with IL-2 and interfiron (IFN), one with endocrine therapy and one with only surgery. We obtained an objective response to maintenance treatment of 50%. Median duration of response was 19 months and median PFS was 33 months. Median duration of maintenance treatment was 12 months, median follow-up duration from diagnosis to June 2003 was 40 months, and median follow-up duration from study entry to June 2003 was 17 months. The median overall survival has not been reached. Toxicity was negligible. As for QL, a significant improvement of cognitive functions was observed, whereas all other functioning and symptom scales did not change significantly. As for laboratory parameters, absolute lymphocyte count increased significantly, IL-6, IL-1 beta, tumor necrosis factor-alpha, CRP, and fibrinogen decreased significantly whereas IL-2 and leptin increased significantly after treatment. ROS decreased significantly, whereas GPx increased significantly after treatment. Patients alive at study end showed a significant increase in absolute lymphocyte count, IL-2, leptin, and GPx and a significant decrease of proinflammatory cytokines, CRP, fibrinogen, and ROS, whereas patients who died before study end exhibited only a significant increase in absolute lymphocyte count, IL-2, and GPx and a significant decrease of ROS. Long-term combined maintenance therapy with rIL-2 + MPA + antioxidant agents is feasible, has a very low toxicity, and results in the improvement of clinical outcome, QL, and laboratory parameters.
 ...
PMID:Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters. 1456 91

There are several genes that code for enzymes, including various forms of superoxide dismutase and glutathione peroxidase, that protect the cell against oxidative damage that, in turn, can lead to carcinogenesis. There are a few common genetic polymorphisms in these genes that lead to altered proteins. Three that have been identified are SOD2 Val-9Ala, GPX1 Pro198Leu, and the GPX1 GCG repeat (three alleles with four, five, or six repeats). The SOD2 variant has been associated with increased breast cancer risk in two studies. The GPX1 variants have not been studied with respect to breast cancer, but Pro198Leu has been associated with lung cancer. We conducted a case-control study of these three polymorphisms in incident, invasive breast cancer in Caucasian women under 55. There were 399 cases and 372 controls genotyped, of whom 488 were premenopausal, 208 postmenopausal, and 75 of unknown menopausal status. We were unable to replicate the previously observed association with SOD2 Val-9Ala and also found no association between breast cancer and GPX1 Pro198Leu. However, the allele of GPX1 containing four GCG repeats was significantly associated with breast cancer risk in premenopausal women (odds ratio, 1.55; 95% confidence interval, 1.04-2.30 for carriers versus noncarriers). There is a significant trend of increasing risk with increasing number of alleles with four GCG repeats (P = 0.03). This variant has not previously been reported to be associated with breast cancer.
 ...
PMID:Genetic variants of GPX1 and SOD2 and breast cancer risk at the Ontario site of the Breast Cancer Family Registry. 1474 47

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.
 ...
PMID:Particulate phase cigarette smoke increases MnSOD, NQO1, and CINC-1 in rat lungs. 1547 4

Lung cancer is a common pathology with high mortality due to late diagnosis. Glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), catalase (CAT), xanthine oxidase (XO), Cu-Zn superoxide dismutase (Cu-Zn SOD) activities, total glutathione (TGSH), nitric oxide (NO*), and malondialdehyde (MDA) levels were investigated in erythrocytes of patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), and healthy control group. We aimed to investigate serum GSH, GSH-dependent enzymes activities (GSH-Px and GST), XO, CAT, Cu-Zn SOD activity, and NO*, and MDA levels in patients with NSCLC and with SCLC and correlate with the cancer stage. Erythrocyte MDA, NO*, TGSH levels and erythrocyte SOD, CAT and XO activities were significantly higher in patients with NSCLC and SCLC than in controls. Slightly increased erythrocyte GSH-Px and GST activities were not significantly different from the controls. Erythrocyte MDA level positively correlated with erythrocyte NO* levels in patients with early stage (I+II) in NSCLC groups. Erythrocyte MDA level positively correlated with erythrocyte XO activity in patients with advanced stage (III+IV) in NSCLC groups. However, no other correlation could be found among the parameters in healthy controls and patients with NSCLC and with SCLC. Results obtained in this study indicate significant changes in antioxidant defence system in NSCLC and SCLC patients, which may lead to enhanced action of oxygen radical, resulting in lipid peroxidation.
 ...
PMID:Glutathione peroxidase, glutathione-S-transferase, catalase, xanthine oxidase, Cu-Zn superoxide dismutase activities, total glutathione, nitric oxide, and malondialdehyde levels in erythrocytes of patients with small cell and non-small cell lung cancer. 1611 16

The present study aimed to determine the alterations of antioxidant activities in erythrocytes from patients with nonsmall cell lung carcinoma (NSCLC). A comparative study of the systemic antioxidant activities in red blood cell lysate from subjects with NSCLC and healthy control subjects was conducted. The antioxidants catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured using chemical kinetic reactions under spectrophotometry. In total, 189 cases of mostly advanced-stage IIIB or stage IV NSCLC and 202 healthy controls were studied. In subjects with lung cancer, there was similar catalase activity, lower SOD activity (median (interquartile range) 13.4 (9.0-27.2) versus 48.7 (27.0-64.3) U x (ghaemoglobulin(Hb)(-1)), and higher GPx activity (175.2 (126.6-288.3) versus 49.2 (39.5-59.2) mU x (gHb)(-1)) compared with controls. The antioxidant activities in lung cancer subjects were not associated with age, sex, smoking status, or tumour cell types. However, more advanced disease (stage IV compared with stage IIIB) was associated with lower SOD activity. Using multivariable analysis, the presence of lung cancer independently predicted SOD and GPx activities. In conclusion, nonsmall cell lung carcinoma in Chinese subjects is associated with alterations in systemic antioxidant activities, which may play an important role in carcinogenesis.
 ...
PMID:Disturbance of systemic antioxidant profile in nonsmall cell lung carcinoma. 1700 88

We found previously that the human lung benzo(a)pyrene (BP)-7,8-diol-9,10-epoxide-N(2)-deoxyguanosine (BPDE-dG) adduct concentrate in the target bronchial cells. This adduct is now considered to be critical event in tumorigenesis by BP. In this study, we investigate the contribution of cigarette smoke on the BPDE-dG formation. In a cell-free system, the amount of (-)-anti-BPDE-dG adduct increased linearly with concentration of cigarette smoke in the presence of (+)-BP-7,8-diol. Catalase and superoxide dismutase inhibited its formation by >80%. When MCF-7 cells were treated for 2 hours with the (+)-BP-7,8-diol, cigarette smoke increased dose dependently the formation of (-)-anti-BPDE-dG and decreased the cytochrome P450 (CYP)-dependent formation of (+)-r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydro-BP the adduct. Then, cells were treated for up to 1 day with BP and then exposed for 2 hours with cigarette smoke. During these 2 hours, there are twice the increase in the adduct formation in cells treated with cigarette smoke compared with levels in nontreated cells due to CYP activity. Thus, cigarette smoke containing reactive oxygen species may activate the second step of BP metabolic way, leading to the formation of BPDE-dG adduct. Cigarette smoke thus seems may be in part responsible for the formation of the critical lung tumorigenic adduct. Finally, modified cigarette filter containing rosemary extract decreases by >70% of the BPDE-dG adducts level due to the cigarette smoke in MCF-7 cells. This approach may lead to decreasing lung cancer risk in addicted smokers.
 ...
PMID:DNA damage by benzo(a)pyrene in human cells is increased by cigarette smoke and decreased by a filter containing rosemary extract, which lowers free radicals. 1717 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>