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

Trypanosomiasis (whether African sleeping sickness, or American Chaga's disease) is caused by an infection with a protozoan parasite, i.e. the trypanosome. This carries fatal sequences in the untreated host. Currently available chemotherapeutic drugs (some of which cure by involving reactive oxygen species (ROS] are not optimally adequate. They are toxic as well, and may also be carcinogenic. It is therefore desirable to devise better chemotherapeutic regimens. ROS destroy the parasite, but excess ROS damage host tissue and are potentially carcinogenic. Alpha-difluoromethylornithine (DFMO) inhibits ornithine decarboxylase and so lowers the levels of spermine and spermidine. This singular effect in the parasite inhibits its multiplication, whereas in the host tissue it prevents carcinogenesis by preventing cell proliferation. Thus, combination of ROS-generating drugs with DFMO would be very effective against trypanosomiasis, and would be without cancer risk too. The combination is therefore advocated for chemotherapy of trypanosoma infections. This necessities experimental investigations specifically directed towards establishing the optimally efficacious combination of DFMO with the drugs.
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PMID:Towards more efficacious chemotherapy of trypanosomiasis: combination of alpha-difluoromethylornithine (DFMO) with reactive oxygen generating drugs. 178 20

To establish an accurate 8-hydroxydeoxyguanosine (8OHdG) determination system, we examined two potential factors causing experimental error in 8OHdG determination. First, we examined the efficiency of the enzymatic digestion of DNA, that could cause misestimation of 8OHdG. Second, since we considered that the oxygen molecules in atmosphere and in reagents were the main factor contributing to the experimental errors, we carried out the 8OHdG determination under oxygen-free conditions and compared the 8OHdG value with that determined by the methods under ambient atmosphere. The calf thymus DNA was sufficiently digested in the condition we used and the yields of dG were constant, even when the DNA was damaged with H2O2 (80 mM) and UV irradiation. By carrying out the DNA extraction manually, instead of using the DNA extractor, we could reduce the additional 8OHdG formation during sample processing. No trend was found in the difference between the 8OHdG values determined under oxygen-free conditions and under ambient atmosphere. However, when the 8OHdG values were compared in samples with asbestos, the value determined under oxygen-free conditions was significantly lower than that determined under ambient atmosphere. These findings suggest that the removal of oxygen molecules was effective in reducing accidental ROS generation by impurities in the sample, which could cause the additional 8OHdG formation, and that the oxygen-free system made the determination of 8OHdG reproducible and more accurate than before. When the oxygen-free system was applied to human leukocytes, the system showed good reproducibility (r = 0.535, P < 0.001), even though the 8OHdG level was low. With the system, we could detect a significant difference between 8OHdG in polymorphonuclear leukocytes (0.241 +/- 0.129) and mononuclear leukocytes (0.188 +/- 0.126, P < 0.01).
Carcinogenesis 1996 Apr
PMID:Determination of 8-hydroxydeoxyguanosine in human cells under oxygen-free conditions. 862 92

Genomic instability has been associated with cancer development. Oxidative DNA damage seems to contribute to genetic instability observed in cancer. We have used human lung cancer cell lines carrying a plasmid vector containing a (CA)(13) microsatellite sequence to study frameshift mutations mediated by ROS-generating chemicals paraquat and hydrogen peroxide. Exposure of the cells to both paraquat and hydrogen peroxide resulted in significantly higher mutation frequencies compared with untreated control cells. Mutation frequencies up to 27-fold higher than the spontaneous mutation frequencies were obtained. The majority of the reversion mutants contained frameshift mutations within the target sequence. However, the pattern of deletions and additions was significantly different in the two cell lines. These results indicate that oxidative damage may play a role in instability of microsatellite sequences in vivo.
Carcinogenesis 2000 Aug
PMID:Induction of microsatellite mutations by oxidative agents in human lung cancer cell lines. 1091 Sep 53

Aflatoxin B(1) (AFB(1)), a potent hepatocarcinogen, enhances ROS formation and causes oxidative DNA damage, which may play a role in its carcinogenicity. We have demonstrated recently that ebselen, an organic selenium compound, protects against the cytotoxicity of AFB(1) through its antioxidant capability. The present study was designed to investigate the effect of ebselen on AFB(1)-induced hepatocarcinogenesis in an animal model. Fischer 344 rats were first treated with either deionized water or ebselen (5 mg/kg, 5 days/week) via gavage for 4 weeks, then given AFB(1) (0.4 mg/kg, gavage, once a week) or AFB(1) plus ebselen (5 mg/kg, 5 days/week) for another 24 weeks. The results showed that the hepatocarcinogenicity of AFB(1) in rats was significantly reduced by ebselen treatment as indicated by a decrease in: (i) serum gamma-glutamyl transpeptidase activity; (ii) expression of mRNAs of liver alpha-fetoprotein and the placental form of glutathione S-transferase (GST-P); and (iii) the area and mean density of staining of liver GST-P foci. Ebselen treatment significantly reduced the formation of hepatic AFB(1)-DNA adducts and 8-hydroxydeoxyguanosine caused by AFB(1) exposure. These findings suggest that ebselen can inhibit the carcinogenicity of AFB(1). In addition to the reduction of AFB(1)-DNA adduct formation, the protective effect of ebselen against AFB(1)-induced oxidative DNA damage may also, at least in part, contribute to its anticarcinogenic property.
Carcinogenesis 2000 Dec
PMID:Inhibition of ebselen on aflatoxin B(1)-induced hepatocarcinogenesis in Fischer 344 rats. 1113 13

Many studies have demonstrated beneficial health effects of topical antioxidant application; however, the underlying mechanisms are not well understood. To better understand the protective mechanism of oxogenous anti-oxidants, it is important to clarify the physiological distribution, activity and regulation of antioxidants. Also, the generation of ROS by the resident and transient microbial flora and their interaction with cutaneous antioxidants appears to be of relevance for the redox properties of skin. Our studies have demonstrated that alpha-tocopherol is, relative to the respective levels in the epidermis, the major antioxidant in the human SC, that alpha-tocopherol depletion is a very early and sensitive biomarker of environmentally induced oxidation and that a physiological mechanism exists to transport alpha-tocopherol to the skin surface via sebaceous gland secretion. Furthermore, there is conclusive evidence that the introduction of carbonyl groups into human SC keratins is inducible by oxidants and that the levels of protein oxidation increase towards outer SC layers. The demonstration of specific redox gradients within the human SC may contribute to a better understanding of the complex biochemical processes of keratinization and desquamation. Taken together, the presented data suggest that, under conditions of environmentally challenged skin or during prooxidative dermatological treatment, topical and/or systemic application of antioxidants could support physiological mechanisms to maintain or restore a healthy skin barrier. Growing experimental evidence should lead to the development of more powerful pharmaceutical and cosmetic strategies involving antioxidant formulations to prevent UV-induced carcinogenesis and photoaging as well as to modulate desquamatory skin disorders.
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PMID:The antioxidant network of the stratum corneum. 1122 99

Several studies have shown the involvement of reactive oxygen species (ROS; O2*-, hypochlorite, hydroxyl radical, hydrogen peroxide) in carcinogenesis. With certain pathologies, nitric oxide (NO) is formed and can interact with superoxide radical (O2*-) resulting in the propagation of the highly reactive species, peroxynitrite. In order to study the molecular mechanisms underlying the ability of reactive oxygen and nitrogen species (RONS) to mediate carcinogenesis, we have measured ROS, NO, and peroxynitrite content of cancerous tissues obtained from colon and breast carcinoma cases by chemiluminescence technique. All ROS were significantly increased in cancerous colon tissues with hypochlorite making the most important contribution and suggesting the role of inflammatory cells. NO was also increased and the peroxynitrite concentration was higher in cancerous samples. For breast carcinoma cases, only O2*- was significantly increased. Hypochlorite was not detected excluding the contribution of inflammatory cells. NO concentrations were not significantly different, therefore, ROS might originate by change in the redox state of the tissue.
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PMID:Different kinds of reactive oxygen and nitrogen species were detected in colon and breast tumors. 1127 72

DNA damage induced by tetrachlorohydroquinone (Cl(4)HQ), the quinonoid metabolite of pentachlorophenol (PCP), was investigated in human HeLa S3 tumor cells. Formation of one major and two minor DNA adducts in cells treated with Cl(4)HQ (50-300 microM) was detected by (32)P-post-labeling assay and the adducts accumulated over the course of the experiment (0.5-2 h), with total adduct levels estimated to be 3-6 per 10(8) nucleotides. These adducts did not correspond to those derived from calf thymus DNA treated with tetrachloro-1,4-benzoquinone. Results from the apurinic/apyrimidinic (AP) sites assay indicated that the number of AP sites was 2-fold greater in cells exposed to Cl(4)HQ (300 microM) than the corresponding control. Further characterization of the AP sites confirmed that Cl(4)HQ induced predominantly (75%) putrescine-excisable AP sites in HeLa S3 cells. In parallel, the concentration of 8-hydroxy-2'-deoxyguanosine (8-HO-dG) in cells treated with Cl(4)HQ for 0.5 and 2 h was increased 2- and 5-fold, respectively, compared with the control. The extent of oxidative DNA damage induced by Cl(4)HQ was approximately two orders of magnitude greater than those of direct DNA adducts. Overall, it appears that reactive oxygen species mediate the parallel formation of AP sites and 8-HO-dG in HeLa S3 cells following treatment with Cl(4)HQ and that the contribution of depurination/depyrimidination of direct DNA adducts is relatively insignificant compared with the formation of oxidized AP sites. We conclude that putrescine-excisable AP sites represent a major type of ROS-mediated oxidative DNA damage in cellular DNA induced by Cl(4)HQ and may play a role in PCP-induced clastogenicity in mammalian cells.
Carcinogenesis 2001 Apr
PMID:Induction of direct adducts, apurinic/apyrimidinic sites and oxidized bases in nuclear DNA of human HeLa S3 tumor cells by tetrachlorohydroquinone. 1128

We reviewed the mechanism of oxidative DNA damage with reference to metal carcinogenesis and metal-mediated chemical carcinogenesis. On the basis of the finding that chromium (VI) induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2), we proposed the hypothesis that endogenous reactive oxygen species play a role in metal carcinogenesis. Since then, we have reported that various metal compounds, such as cobalt, nickel, and ferric nitrilotriacetate, directly cause site-specific DNA damage in the presence of H2O2. We also found that carcinogenic metals could cause DNA damage through indirect mechanisms. Certain nickel compounds induced oxidative DNA damage in rat lungs through inflammation. Endogenous metals, copper and iron, catalyzed ROS generation from various organic carcinogens, resulting in oxidative DNA damage. Polynuclear compounds, such as 4-aminobiphenyl and heterocyclic amines, appear to induce cancer mainly through DNA adduct formation, although their N-hydroxy and nitroso metabolites can also cause oxidative DNA damage. On the other hand, mononuclear compounds, such as benzene metabolites, caffeic acid, and o-toluidine, should express their carcionogenicity through oxidative DNA damage. Metabolites of certain carcinogens efficiently caused oxidative DNA damage by forming NADH-dependent redox cycles. These findings suggest that metal-mediated oxidative DNA damage plays important roles in chemical carcinogenesis.
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PMID:The role of metals in site-specific DNA damage with reference to carcinogenesis. 1197 84

The focus of this review is to provide state-of-the-art knowledge on the involvement of oxygen free radicals (OFR) in carcinogenesis with a particular reference to skin model system as the process of cancer development is best understood in this organ. However, a brief description of the role of OFR in other organs is also provided. The term OFR refers to forms of oxygen exhibiting high reactivity and having at least one unpaired electron. The role of OFR in different stages of carcinogenesis such as initiation, promotion and progression is described. Out of many mechanisms described for the chemical initiation of tumorigenesis, a number of them may involve free radicals in the cascade of reactions. Evidences that support the involvement of free radicals in tumor promotion include (i) a number of free radical-generating compounds are found to be tumor promoters in various animal model systems, (ii) ROS generating systems can mimic the biochemical action of tumor promoters, (iii) some tumor promoters stimulate the production of ROS, (iv) tumor promoters modulate the cellular antioxidant defense systems, and (v) free radical scavengers, detoxifiers and antioxidants inhibit the process of tumor promotion. The role of ROS in the progression stage of carcinogenesis is evident from the fact that a number of different free radical generating compounds enhance the malignant conversion of benign papillomas into carcinoma and their effectiveness may be related to the type of radicals produced into the biological system.
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PMID:Oxidative stress and experimental carcinogenesis. 1258 14

We recently developed a short-term assay for skin H2O2 generation induced by double 12-O-tetradecanoylphorbol-13-acetate (TPA) applications for mechanistic study on skin epidermal carcinogenesis. In the present study, we investigated the individual roles of arachidonic acid metabolism in H2O2 generation in mouse skin inflammation. The experiments using inhibitors of arachidonic acid (AA) metabolism showed that corticosteroid and a lipoxygenase (LO) inhibitor expectedly suppressed double TPA application-induced H2O2 generation through the interference of chemotactic action but not by direct decomposition or scavenging. We also demonstrated that the treatment of AA (1 mumol) and 5-LO metabolites including leukotriene B4 (LTB4) partly mimicked, though soybean LO-derived lipid hydroperoxide and prostaglandins did not, the priming effect evaluated by edema formation and leukocyte infiltration. We also confirmed that inflammatory leukocytes accumulated by LTB4 generated a significant amount of H2O2 by TPA stimulation. These results suggested that 5-LO metabolites of AA are the potential key molecules in the TPA-induced priming event. Interestingly, the cyclooxygenase (COX-) 2-selective inhibitor nimesulide (NS) and celecoxib (CXB) showed different responses than those of other inhibitors. These agents showed no specific potential to inhibit the priming event but significantly suppressed H2O2 generation, lipid peroxidation, and hyperplasia in mouse skin. From the results based on an in vitro leukocyte differentiation model, we speculated that the antioxidant effect of the COX-2 inhibitors might be partly associated with both counteraction of proinflammatory cytokine-enhanced ROS generation and inhibition of CD11b, an important molecule for cell adhesion, expression. Indeed, the topical application of NS attenuated the number of infiltrated leukocytes induced by TPA in mouse skin. Thus, these gathered data indicated the differential roles of 5-LO and COX-2 in leukocyte adhesion, infiltration, and H2O2 generation.
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PMID:Arachidonic acid cascade inhibitors modulate phorbol ester-induced oxidative stress in female ICR mouse skin: differential roles of 5-lipoxygenase and cyclooxygenase-2 in leukocyte infiltration and activation. 1457 3


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