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61.
Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis 总被引:1,自引:0,他引:1
During chronic inflammatory processes an excess of free radicals and DNA-reactive aldehydes from lipid peroxidation (LPO) are produced, which deregulate cellular homeostasis and can drive normal cells to malignancy. Etheno (epsilon)-modified DNA bases are generated by reactions of DNA with a major LPO product, trans-4-hydroxy-2-nonenal. We investigated steady state levels of epsilon-DNA adducts in organs, blood or urine from patients with cancer prone diseases, especially when related to persistent inflammatory processes. We have developed sensitive and specific methods for adduct detection in vivo. Hepatic etheno-adduct levels were significantly elevated in patients with Wilson's disease and primary hemochromatosis. Excess storage of copper/iron causing oxidative stress and LPO-derived DNA-damage, are implicated in disease pathogenesis as confirmed by studies in LEC-rats, a model for Wilson's disease. When patients with alcohol related hepatitis, fatty liver, fibrosis and cirrhosis were compared with asymptomatic livers, excess hepatic DNA-damage was seen in all patients, except those with hepatitis. Etheno-deoxyadenosine excreted in urine was measured in HBV-infected patients diagnosed with chronic hepatitis, cirrhosis and hepatocellular carcinoma: as compared to controls, patients had 20-90-fold increased urinary levels. In conclusion: epsilon-DNA adducts may serve as potential markers for assessing progression of inflammatory cancer-prone diseases. Also the efficacy of human chemopreventive interventions could be verified by using our non-invasive urine assay. Mechanisms and host-factors that influence the steady-state levels of epsilon-DNA adducts in cancer prone tissues are under investigation. 相似文献
62.
Nair J Godschalk RW Nair U Owen RW Hull WE Bartsch H 《Chemical research in toxicology》2012,25(1):162-169
Methylation of cytidine at dCpdG sequences regulates gene expression and is altered in many chronic inflammatory diseases. Inflammation generates lipid peroxidation (LPO) products which can react with deoxycytidine, deoxyadenosine, and deoxyguanosine in DNA to form pro-mutagenic exocyclic etheno-nucleoside residues. Since 5-methyl-2'-deoxycytidine (5mdC) residues exhibit increased nucleophilicity at N3, they should be even better targets for LPO products. We synthesized and characterized 3,N(4)-etheno-5-methyl-2'-deoxycytidine-3'-phosphate and showed that LPO products can indeed form the corresponding etheno-5mdC (ε5mdC) lesion in DNA in vitro. Our newly developed (32)P-postlabeling method was subsequently used to detect ε5mdC lesions in DNA from human white blood cells, lung, and liver at concentrations 4-10 times higher than that observed for etheno adducts on nonmethylated cytidine. Our new detection method can now be used to explore the hypothesis that this DNA lesion perturbs the DNA methylation status. 相似文献
63.
Tobacco smoke contains many alkylating agents that can react with DNA to produce O(4)-ethylthymidine (O(4)-etT) and several other types of promutagenic base modifications. Our aims were (i) to confirm results of a pilot study (Godschalk, R., Nair, J., Schooten, F. J., Risch, A., Drings, P., Kayser, K., Dienemann, H. and Bartsch, H. (2002) Comparison of multiple DNA adduct types in tumor adjacent human lung tissue: effect of cigarette smoking. Carcinogenesis, 23, 2081-2086) on the formation of O(4)-etT in smokers' lung; (ii) to explore associations between levels of O(4)-etT and smoking status and (iii) to investigate whether a correlation exists between levels of O(4)-etT and bulky (polycyclic aromatic hydrocarbons-derived) DNA adducts. Archived DNA samples originated from histologically normal peripheral lung tissues of 64 Hungarian lung cancer patients, who underwent lung resection. O(4)-etT was determined by an immunoenriched (32)P-postlabelling-high-performance liquid chromatography method. Levels of bulky DNA adducts were determined by the nuclease P1 adduct-enriched (32)P-postlabelling. O(4)-etT levels ranged from 0.01 to 3.91 adducts/10(8) thymidines. In the combined group of subjects who smoked until surgery or gave up smoking at most 1 year before it, the mean level of O(4)-etT was 1.7-fold (P = 0.015) and of bulky DNA adducts 2.2-fold (P < 0.0001) higher than in long-term ex-smokers (LES) and never-smokers (NS) combined. We found no significant correlation between the individual levels of the two DNA adduct types. No dose-response was detected between O(4)-etT formation and smoking dose. In one-third of LES, O(4)-etT levels were above the 2.0-fold mean level of adducts found in NS, indicating its high persistence. Our results confirm the smoking-related formation of O(4)-etT in human lung DNA that should be explored as biomarker. Its long persistence in target tissue implicates a role of this potentially miscoding lesion in tobacco smoking-associated cancers. 相似文献
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Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxyl radical generation during betel quid chewing 总被引:2,自引:1,他引:1
Nair Urmila J.; Nair Jagadeesan; Friesen Marlin D.; Bartsch Helmut; Ohshima Hiroshi 《Carcinogenesis》1995,16(5):1195-1198
The habit of betel quid chewing, common in South-East Asia andthe South Pacific islands, is causally associated with an increasedrisk of oral cancer. Reactive oxygen species formed from polyphenolicbetel quid ingredients and lime at alkaline pH have been implicatedas the agents responsible for DNA and tissue damage. To determinewhether hydroxyl radical (HO) is generated in the human oralcavity during chewing of betel quid, the formation of o- andm-tyrosine from L-phenylalanine was measured, Both o- and m-tyrosinewere formed in vitro in the presence of extracts of areca nutand/or catechu, transition metal ions such as Cu2+ and Fe2+and lime or sodium carbonate (alkaline pH). Omission of anyof these ingredients from the reaction mixture significantlyreduced the yield of tyrosines. Hydroxyl radical scavengerssuch as ethanol, D-mannitol and dimethylsulfoxide inhibitedthe phenylalanine oxidation in a dose-dependent fashion. Fivevolunteers chewed betel quid consisting of betel leaf, arecanut, catechu and slaked lime (without tobacco). Their saliva,collected after chewing betel quid, contained high concentrationsof p-tyrosine, but no appreciable amounts of o- or m-tyrosine.Saliva samples from the same subjects after chewing betel quidto which 20 mg phenylalanine had been added contained o- andm-tyrosine at concentrations ranging from 1010 to 3000 nM andfrom 1110 to 3140 nM respectively. These levels were significantlyhigher (P< 0.005) than those of subjects who kept phenylalaninein the oral cavity without betel quid, which ranged from 14to 70 nM for o-tyrosine and from 10 to 35 nM for m-tyrosine.These studies clearly demonstrate that the HO radical is formedin the human oral cavity during betel quid chewing and is probablyimplicated in the genetic damage that has been observed in oralepithelial cells of chewers. 相似文献
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70.
Kumar S Suresh PK Vijayababu MR Arunkumar A Arunakaran J 《Journal of ethnopharmacology》2006,105(1-2):246-250
Prostate cancer (PC) is the most prevalent cancer and the leading cause of male cancer death. Azadirachta indica (neem tree) has been used successfully centuries to reduce tumors by herbalists throughout Southeast Asia. Here the present study indicated that an ethanolic extract of neem has been shown to cause cell death of prostate cancer cells (PC-3) by inducing apoptosis as evidenced by a dose-dependent increase in DNA fragmentation and a decrease in cell viability. Western blot studies indicated that treatment with neem extract showed decreased level of Bcl-2, which is anti-apoptotic protein and increased the level of Bax protein. So the neem extract could be potentially effective against prostate cancer treatment. 相似文献