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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Compelling experimental and epidemiological evidence involves oxygen radicals in carcinogenesis, acting reactive oxygen species both as endogenous genotoxins during cell initiation and as messenger molecules in mitogenesis and in tumor promotion. Moreover, oxidants stimulate neoangiogenesis, which is a prerequisite for tumor growth. However, while several natural as well as synthetic antioxidant compounds appear to be chemopreventive in mutagenicity assays, antioxidant-based treatments for the prevention or cure of cancer have led to non-conclusive if not disappointing results. This is likely due to the fact that oxygen radicals have also a major role in the natural defences against the propagation of cancer cells, i.e. tumor cell apoptosis and immune surveillance, and mediate the beneficial cytotoxic effect of both the chemo-and radio-therapy. In recent years, the mitochondrial antioxidant enzyme, Manganous Superoxide Dismutase (MnSOD), has received a growing attention as a negative modulator of cellular apoptosis and as a survival factor for cancer cells. In fact, while overexpression of this enzyme in cancer cells decreases proliferation and tumor incidence in transgenic models, it is clear that even small amounts of this enzyme are crucial for cell resistance to inflammatory stimuli and anticancer drugs, and prevent oncogene-induced apoptosis triggered by the tumor suppressor protein p53. A previously unexpected oncogenic potential of MnSOD is also suggested by the elevated levels of this enzyme in several classes of human neoplasms, in a fashion which often correlates with the degree of their malignancy. This review focuses on the debated issue of the pro- and/or anti-tumoral effect of MnSOD, with special emphasis on recent observations suggesting that pharmacological inhibition of MnSOD may represent an effective strategy to selectively kill cancer cells and to circumvent their resistance to the commonly used anticancer treatments.
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PMID:Mitochondrial superoxide dismutase: a promising target for new anticancer therapies. 1513 21

Reactive Oxygen Species (ROS) result from cell metabolism as well as from extracellular processes. ROS exert some functions necessary for cell homeostasis maintenance. When produced in excess they play a role in the causation of cancer. ROS mediated lipid peroxides are of critical importance because they participate in chain reactions that amplify damage to biomolecules including DNA. DNA attack gives rise to mutations that may involve tumor suppressor genes or oncogenes, and this is an oncogenic mechanism. On the other hand, ROS production is a mechanism shared by many chemotherapeutic drugs due to their implication in apoptosis control. The ROS mediated cell responses depend on the duration and intensity of the cells exposing to the increased ROS environment. Thus the status redox is of great importance for oncogenetic process activation and it is also implicated in tumor susceptibility to specific chemotherapeutic drugs. Phospholipid Hydroperoxide Glutathione Peroxidase (PH-GPx) is an antioxidant enzyme that is able to directly reduce lipid peroxides even when they are bound to cellular membranes. This article will review the relevance of oxidative stress, particularly of lipid peroxidation, in cell response with special focus in carcinogenesis and cancer therapy that suggests PH-GPx as a potentially important enzyme involved in the control of this processes.
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PMID:Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain). 1528 Jun 29

The present study was carried out to study the effect of gentisic acid (2,5-dihydroxybenzoic acid (2,5-DHBA)) on the tumor promotion related events of carcinogenesis in murine skin. Benzoyl peroxide (BPO) (20 mg/0.2 ml/animal) and ultraviolet radiations (UVR) (0.420 J/m2/s) were used to induce tumor promotion response and oxidative stress and caused significant depletion in the detoxification and antioxidant enzyme armory with concomitant elevation in malondialdehyde (MDA) formation, hydrogen peroxide (H2O2) generation, ornithine decarboxylase (ODC) activity and unscheduled DNA synthesis. However, gentisic acid pretreatment at two different doses restored the levels of the above said parameters (P < 0.05) in a dose-dependent manner except in the case of ODC activity. Therefore, we propose that it might suppress the promotion stage via inhibition of oxidative stress but may not affect the polyamine biosynthetic pathway.
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PMID:Modulatory effect of gentisic acid on the augmentation of biochemical events of tumor promotion stage by benzoyl peroxide and ultraviolet radiation in Swiss albino mice. 1545 5

Oxidative stress may enhance prostatic carcinogenesis. A polymorphism [valine (V) --> alanine (A)] of manganese superoxide dismutase (MnSOD), the primary antioxidant enzyme in mitochondria, has been recently associated with prostate cancer. We examined the relationship between prostate cancer and the MnSOD polymorphism and its interactions with baseline plasma antioxidant levels (selenium, lycopene, and alpha-tocopherol) and beta-carotene treatment among 567 cases and 764 controls nested in the prospective Physicians' Health Study. We found little overall association between MnSOD polymorphism and prostate cancer risk; however, this polymorphism significantly modified risk of prostate cancer associated with prediagnostic plasma antioxidants (P(interaction) > or = 0.05). Among men with the AA genotype, high selenium level (4th versus 1st quartile) was associated with a relative risk (RR) of 0.3 [95% confidence interval (CI), 0.2-0.7] for total prostate cancer; for clinically aggressive prostate cancer, the RR was 0.2 (95% CI, 0.1-0.5). In contrast, among men with the VV/VA genotype, the RRs were 0.6 (0.4-1.0) and 0.7 (0.4-1.2) for total and clinically aggressive prostate cancer. These patterns were similar for lycopene and alpha-tocopherol and were particularly strong when these antioxidants and selenium were combined; men with the AA genotype had a 10-fold gradient in risk for aggressive prostate cancer across quartiles of antioxidant status. Men with AA genotype who were randomly assigned to beta-carotene treatment (versus placebo) had a RR of 0.6 (95% CI, 0.2-0.9; P(interaction) = 0.03) for fatal prostate cancer, but no significant association was observed in men with the VV/VA genotype. Both endogenous and exogenous antioxidants play an important and interdependent role in preventing clinically significant prostate cancer.
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PMID:Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. 1578 67

Tamoxifen citrate is an anti-estrogenic drug used for the treatment of breast cancer. It showed a degree of hepatic carcinogenesis, when it used for long term as it can decrease the hexose monophosphate shunt and thereby increasing the incidence of oxidative stress in liver rat cells leading to liver injury. In this study, a model of liver injury in female rats was done by intraperitoneal injection of tamoxifen in a dose of 45 mg/kg body weight for 7 successive days. This model produced a state of oxidative stress accompanied with liver injury as noticed by significant declines in the antioxidant enzymes (glutathione-S-transferase, glutathione peroxidase and catalase) and reduced glutathione concomitant with significant elevations in TBARS (thiobarbituric acid reactive substance) and liver transaminases; sGPT (serum glutamate pyruvate transaminase) and sGOT (serum glutamate oxaloacetate transaminase) levels. The oral administration of dimethyl dimethoxy biphenyl dicarboxylate (DDB) in a dose of 200 mg/kg body weight daily for 10 successive days, resulted in alleviation of the oxidative stress status of tamoxifen-intoxicated liver injury in rats as observed by significant increments in the antioxidant enzymes (glutathione-S-transferase, glutathione peroxidase and catalase) and reduced glutathione concomitant with significant decrements in TBARS and liver transaminases; sGPT and sGOT levels. The administration of DDB before tamoxifen intoxication (as protection) is more little effective than its curative effect against tamoxifen-induced liver injury. The data obtained from this study speculated that DDB can mediate its biochemical effects through the enhancement of the antioxidant enzyme activities and reduced glutathione level as well as decreasing lipid peroxides.
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PMID:The effect of dimethyl dimethoxy biphenyl dicarboxylate (DDB) against tamoxifen-induced liver injury in rats: DDB use is curative or protective. 1594 5

It is reported that the water extract of tea as well as tea polyphenols and tea pigments have strong antioxidant properties, which are considered as the major mechanism of the protective effects of tea on cancer and cardiovascular diseases. It has been shown that tea (including tea polyphenols and tea pigments) could induce the antioxidant enzyme activities, regulate phase I and II metabolic enzymes, inhibit the metabolic activation of carcinogens, reduce the formation of carcinogen DNA adducts, inhibit the expression and replication of oncogenes, directly affect the activity of transcription factors, and block the initiation of carcinogenesis, so as to eliminate and alleviate the damage to cellular communication caused by oxidative stress, and eventually prevent the abnormal proliferation of tumor cells. The mechanisms of the protective effects of tea on cardiovascular diseases are possibly related to its effects on the inhibition of lipid oxidation and quenching oxygen and hydroxy free radicals. It was demonstrated that tea pigments could inhibit the oxidation of LDL cholesterol and the adhesion of blood vessel endothelium cells, lower endothelin levels, enhance GSH-PX activities, prevent from blood coagulation and platelet aggregation, and facilitate fibrinogen dissolution, so as to prevent atherosclerosis of coronary arteries.
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PMID:[Studies on the antioxidant properties of tea]. 1595 73

An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. It is well known that chemical carcinogenesis is multistage process. Free radicals arefound to be involved in both initiation and promotion of multistage carcinogenesis. Tamoxifen (TAM) is a potent antioxidant and a non-steroidal antiestrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Besides its anticarcinogenic potential, it also produces some adverse toxic side effects, while taken for a long time. In order to minimise the side effects and to improve the antioxidant efficacy of tamoxifen, coenzyme Q10 (CoQ10) was added. Hence the present study was designed to investigate the combined efficacy of TAM along with CoQ10 in 7, 12 dimethyl benz(a)anthracene (DMBA) induced peroxidative damage in rat mammary carcinoma. The experimental setup comprised of one control and five experimental groups and it was carried out in adult female Sprague-Dawley rats. Mammary carcinoma was induced by oral administration of DMBA (25 mg kg(-1) body wt) and the treatment was started by the oral administration of TAM (10 mg kg(-1) body wt day(-1)) and CoQ10 (40 mg kg(-1) body wt day(-1)) dissolved in olive oil and continued for 28 days. Rats induced with DMBA showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde content levels along with lowered activities of antioxidant status (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione). In contrast, glutathione metabolising enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) were increased significantly in chemically induced carcinoma bearing rats. Administration of TAM along with CoQ10 restored the activities to a significant level thereby preventing cancer cell proliferation. This study highlights the increased antioxidant enzyme activities in relation to the susceptibility of cells to carcinogenic agents and the response of tumour cells to the chemotherapeutic agents.
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PMID:Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer. 1601 50

Catalase is a highly conserved heme-containing antioxidant enzyme known for its ability to degrade hydrogen peroxide into water and oxygen. In low concentrations of hydrogen peroxide, the enzyme also exhibits peroxidase activity. We report that mammalian catalase also possesses oxidase activity. This activity, which is detected in purified catalases, cell lysates, and intact cells, requires oxygen and utilizes electron donor substrates in the absence of hydrogen peroxide or any added cofactors. Using purified bovine catalase and 10-acetyl-3,7-dihydroxyphenoxazine as the substrate, the oxidase activity was found to be temperature-dependent and displays a pH optimum of 7-9. The Km for the substrate is 2.4 x 10(-4) m, and Vmax is 4.7 x 10(-5) m/s. Endogenous substrates, including the tryptophan precursor indole, the neurotransmitter precursor beta-phenylethylamine, and a variety of peroxidase and laccase substrates, as well as carcinogenic benzidines, were found to be oxidized by catalase or to inhibit this activity. Several dietary plant micronutrients that inhibit carcinogenesis, including indole-3-carbinol, indole-3-carboxaldehyde, ferulic acid, vanillic acid, and epigallocatechin-3-gallate, were effective inhibitors of the activity of catalase oxidase. Difference spectroscopy revealed that catalase oxidase/substrate interactions involve the heme-iron; the resulting spectra show time-dependent decreases in the ferric heme of the enzyme with corresponding increases in the formation of an oxyferryl intermediate, potentially reflecting a compound II-like intermediate. These data suggest a mechanism of oxidase activity involving the formation of an oxygen-bound, substrate-facilitated reductive intermediate. Our results describe a novel function for catalase potentially important in metabolism of endogenous substrates and in the action of carcinogens and chemopreventative agents.
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PMID:Characterization of the oxidase activity in mammalian catalase. 1607 30

Allelic losses on chromosome 1p are frequent in hepatocellular carcinoma (HCC), suggesting the presence of a tumour suppressor gene in this region. The gene for peroxiredoxin 1 (PRDX1), an antioxidant enzyme, has been mapped to 1p34.1. Mice lacking PRDX1 develop HCC with high frequency. Because oxidative stress has been implicated in the pathogenesis of HCC, this study was designed to determine whether the PRDX1 gene is mutated in human HCC using loss of heterozygosity (LOH) analysis, polymerase chain reaction/denaturing gradient gel electrophoresis, and DNA sequencing. LOH of at least one of four microsatellite markers within 0.8 Mb of the PRDX1 gene was seen in three of 34 informative HCCs, but no mutations or polymorphisms in the translated exons 2-6 of the PRDX1 gene were found. These results suggest that genetic alterations of the PRDX1 locus are rare events in human HCC, indicating that other genes on chromosome 1p contribute to liver carcinogenesis.
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PMID:Rare allelic imbalances, but no mutations of the PRDX1 gene in human hepatocellular carcinomas. 1625 21

Breast cancer may be related to oxidative stress. Breast cancer patients have been reported to have lower antioxidant enzyme activity than healthy controls and the polymorphism GPX1 Pro198Leu has been associated with risk of lung and breast cancer. The purpose of the present nested case-control study was to determine whether GPX1 Pro198Leu and glutathione peroxidase (GPX) activity in prospectively collected blood samples are associated with breast cancer risk among postmenopausal women and whether GPX activity levels are associated with other known breast cancer risk factors. We matched 377 female breast cancer cases with 377 controls all nested within the prospective 'Diet, Cancer and Health' study of 57 000 Danes. Carriers of the variant T-allele of GPX1 Pro198Leu were at 1.43-fold higher risk of breast cancer compared with non-carriers (95% CI=1.07-1.92). Pre-diagnostic GPX activity tended to be lower in cases compared with controls. GPX activity was positively correlated with intake of alcohol (P<0.0001) and the catalytic activity was lowered 5% for each additional copy of the variant T-allele (P=0.0003). Alcohol intake was correlated with increased GPX activity for the C-allele but not for the T-allele. Results from this prospective study suggest that the GPX1 Pro198Leu-associated lowered GPX activity is associated with higher breast cancer risk among Danish women.
Carcinogenesis 2006 Apr
PMID:Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study. 1628 77


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