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

In this study, we show that the toxicity of ferric nitrilotriacetate (Fe-NTA) can be correlated with the tissue accumulation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts. It is observed that the toxic manifestations of Fe-NTA gradually increase with the increasing age of animals. A dose of Fe-NTA which produces almost 100% mortality in aged rats causes 70% mortality in adults, 30% in pups, 20% in litters, and less than 10% in neonates. The age-dependent increase in its toxicity is also evident from the data of renal microsomal lipid peroxidation and hydrogen peroxide generation. No significant difference in the generation of H2O2 and induction of renal microsomal lipid peroxidation between saline- and Fe-NTA-treated neonates, litters, and pups could be observed. However, in adult rats, a significant increase in both of the parameters was observed which was even greater in aged rats. On the contrary, renal glutathione levels in these animals show an inverse relationship with the oxidant generation. In neonates, litters, and pups the maximum decrease of glutathione was up to 22%, whereas in adult and aged rats, the depletion was more than 60% of their respective saline-treated controls. Parallel to this data, blood urea nitrogen and creatinine, the indicators of renal damage, show a significant increase in Fe-NTA-treated adult and aged rats only, whereas no significant alterations were observed in other groups. Similarly, the magnitude of ODC induction and [3H]thymidine incorporation was much higher in aged and adult rats in comparison to other groups of animals after Fe-NTA treatment. Additionally, the immunohistochemical localization studies show a significant increase in HNE-modified protein adducts in kidney of adult and aged rats, whereas no significant staining was observed in other groups. A similar increase in the level of protein carbonyls has also been observed with the increasing age of rats. These data suggest that the toxicity of Fe-NTA increases with the increasing age of rats and correlates with the accumulation of HNE-modified protein adducts. It may also be speculated that Fe-NTA-mediated renal toxicity leading to carcinogenesis may be related to the tissue accumulation of HNE-modified protein adducts. However, further studies are needed to establish a definite role of HNE-modified proteins in Fe-NTA-mediated carcinogenesis.
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PMID:Age-dependent renal accumulation of 4-hydroxy-2-nonenal (HNE)-modified proteins following parenteral administration of ferric nitrilotriacetate commensurate with its differential toxicity: implications for the involvement of HNE-protein adducts in oxidative stress and carcinogenesis. 1022 44

Ferula (a genus of many species) commonly known as asafoetida is used as a flavoring agent in food and is used as a traditional medicine for many diseases in many parts of world. In the current investigation, we report the antioxidant and anticarcinogenic potential of asafoetida (Ferula narthex) in swiss albino mice. A single dose of TPA (20 nmol/0.2 ml acetone/animal), a known tumor promoter decreased the cellular antioxidant level significantly (p<0.01) when applied topically to mice skin. It also induced the ODC activity, rate of DNA synthesis, hydrogen peroxide level, xanthine oxidase activity and protein carbonyl content in mice skin significantly (p<0.01). These events are early biomarkers of carcinogenesis. However, the pretreatment of animals with asafoetida (300, 400 and 500 microg/200 microl acetone/animal) caused the reversal of all events significantly (p<0.01). The pretreament of animals with asafoetida recovered the antioxidant level and reversed the induced ODC activity and DNA synthesis significantly (p<0.01). We conclude that asafoetida is a potent antioxidant and can afford protection against free radical mediated diseases such as carcinogenesis.
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PMID:Asafoetida inhibits early events of carcinogenesis: a chemopreventive study. 1129 69

Recent advances in our knowledge of arsenic carcinogenesis include the development of rat or mouse models for all human organs in which inorganic arsenic is known to cause cancer-skin, lung, urinary bladder, liver, and kidney. Tumors can be produced from either promotion of carcinogenesis protocols (mouse skin and lungs, rat bladder, kidney, liver, and thyroid) or from complete carcinogenesis protocols (rat bladder and mouse lung). Experiments with p53(+/-) and K6/ODC transgenic mice administered dimethylarsinic acid or arsenite have shown some degree of carcinogenic, cocarcinogenic, or promotional activity in skin or bladder. At present, with the possible exception of skin, the arsenic carcinogenesis models in wild-type animals are more highly developed than in transgenic mice. Recent advances in arsenic metabolism have suggested that methylation of inorganic arsenic may be a toxification, rather than a detoxification, pathway and that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid and dimethylarsinous acid, have a great deal of biological activity. Accumulating evidence indicates that these trivalent, methylated, and relatively less ionizable arsenic metabolites may be unusually capable of interacting with cellular targets such as proteins and even DNA. In risk assessment of environmental arsenic, it is important to know and to utilize both the mode of carcinogenic action and the shape of the dose-response curve at low environmental arsenic concentrations. Although much progress has been recently made in the area of arsenic's possible mode(s) of carcinogenic action, a scientific concensus has not yet been reached. In this review, nine different possible modes of action of arsenic carcinogenesis are presented and discussed-induced chromosomal abnormalities, oxidative stress, altered DNA repair, altered DNA methylation patterns, altered growth factors, enhanced cell proliferation, promotion/progression, gene amplification, and suppression of p53.
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PMID:Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. 1131 54

Several substances interfering with colorectal carcinogenesis may reduce or prevent adenoma formation in familial adenomatous polyposis (FAP), an inherited predisposition to colorectal cancer. This study determined the expression of genes coding for putative anticancer targets (COX-2, iNOS, MMP-7, ODC, PKCbeta, PPARgamma, RXRalpha, RXRbeta, RXRgamma) in FAP patients to provide one of the rationales for the design of chemotherapy and -prevention strategies. Gene expression was assessed by TaqMan analysis in colonic tissue of 9 FAP patients with mutations in the APC gene (APCpos), 5 FAP patients without identified genetic defect (APCneg), and 3 healthy individuals. Among the examined genes, PKCbeta and MMP-7 were most consistently altered in adenoma tissue relative to matched mucosa. Intriguingly, ODC was clearly overexpressed in polyps from APCpos but not APCneg patients. Furthermore, PKCbeta, MMP-7, ODC, and COX-2 as well as all RXRs displayed altered expression in apparently healthy FAP mucosa as opposed to that of healthy individuals. Our data suggests PKCbeta and MMP-7 to be the most suited as anticancer targets among the genes studied.
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PMID:Expression of putative anticancer targets in familial adenomatous polyposis and its association with the APC mutation status. 1171 87

Vitis vinifera (grapes) is used as a fruit worldwide and known for its pharmacological properties. The present paper assesses the chemopreventive potential of Vitis vinifera against 12-O-tetradecanoyl-13-phorbol acetate (TPA)-mediated tumor promotion in 7,12-dimethyl-benz[a]anthracene (DMBA) initiated mice skin. Skin tumor initiation was achieved by a single topical application of DMBA (40 microg/animal/0.20 ml acetone) to mice. Two weeks after the initiation, promoting agent, TPA (5.0 microg/animal/0.2 ml acetone) was applied two times a week for 20 weeks. Pretreatment of Vitis vinifera 1h prior to each application of TPA resulted in protection against cutaneous tumorigenesis in dose-dependent manner. This inhibition was evident when tumor data was considered as the percentage of mice with tumor and the number of tumors per mouse. We have shown that typical application of Vitis vinifera prior to that of TPA resulted in significant inhibition against TPA-caused induction of epidermal ODC activity (P<0.001) and DNA synthesis. Application of Vitis vinifera at a dose level of 5.0 mg and 10.0 mg kg(-1) body weight in acetone prior to that of TPA treatment resulted in partial significant inhibition of oxidative stress in dose-dependent manner. The concomitant increase in the microsomal lipid peroxidation and xanthine oxidase activities were significantly reduced (P<0.001). In addition, the depleted level of glutathione and inhibited activities of antioxidant enzymes were recovered to the partial significant level. Hence, it can be suggested that Vitis vinifera can be used as a chemopreventive agent against oxidative stress and carcinogenesis.
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PMID:Chemopreventive effect of Vitis vinifera extract on 12-O-tetradecanoyl-13-phorbol acetate-induced cutaneous oxidative stress and tumor promotion in murine skin. 1245 31

The clinical applicability of the experimental data discussed previously remains questionable, and results of clinical studies on chemoprevention in Barrett's esophagus are needed. The utility of selectively targeting acid exposure, ODC, and COX-2 is not clear, and elucidation of that role will be facilitated by a better understanding of the contribution of these factors in the development of Barrett's cancers. The insights already gained into the basic mechanisms of acid exposure, ODC, and COX-2 in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma hold promise for the development of future therapies aimed at these molecular targets and their signaling pathways. In preclinical studies, the ability of COX-2 selective NSAIDs and DFMO to inhibit carcinogenesis is encouraging. Results of well-designed, prospective clinical studies, however, are still needed to establish the efficacy of potent acid suppression, COX-2 inhibitors, and DFMO in the prevention of this malignancy.
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PMID:Barrett's esophagus: chemoprevention. 1462 99

Pancreatic cancer is an exceptionally aggressive disease, the treatment of which has largely been unsuccessful due to higher resistance offered by pancreatic cancer cells to conventional approaches such as surgery, radiation and/or chemotherapy. The aberration of Ras oncoprotein has been linked to the induction of multiple signaling pathways and to the resistance offered by pancreatic cancer cells to apoptosis. Therefore, there is a need for development of new and effective chemotherapeutic agents which can target multiple pathways to induce responsiveness of pancreatic cancer cells to death signals. In this study, human pancreatic adenocarcinoma cells AsPC-1 were used to investigate the effect of Lupeol on cell growth and its effects on the modulation of multiple Ras-induced signaling pathways. Lupeol caused a dose-dependent inhibition of cell growth as assessed by MTT assay and induction of apoptosis as assessed by flow cytometry, fluorescence microscopy and western blotting. Lupeol treatment to cells was found to significantly reduce the expression of Ras oncoprotein and modulate the protein expression of various signaling molecules involved in PKCalpha/ODC, PI3K/Akt and MAPKs pathways along with a significant reduction in the activation of NFkappaB signaling pathway. Our data suggest that Lupeol can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of pancreatic cancer cells. Lupeol could be a potential agent against pancreatic cancer, however, further in-depth in vivo studies are warranted.
Carcinogenesis 2005 Nov
PMID:Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway. 1595 16

We have previously reported that Tamarix gallica caused a marked inhibition of thioacetamide-induced hepatotoxicity, oxidative damage and early tumor promotion related events in the liver. These results strongly indicates that T. gallica may have chemopreventive potential. Therefore, in the present study, we examined the inhibitory effects of T. gallica methanolic extract on diethylnitrosamine (DEN) initiated and 2-acetyl aminofluorene (2-AAF) promoted liver carcinogenesis in male Wistar rats. Interestingly, it was found that T. gallica (25 and 50 mg/kg body wt.) resulted in a marked reduction of the incidence of liver tumors. The study was further histologically confirmed. Furthermore to understand the underlying mechanisms of chemopreventive action by T. gallica we evaluated the levels activities of hepatic antioxidant defense enzymes, ornithine decarboxylase activity and hepatic DNA synthesis as a marker for tumor promotion since direct correlation between these marker parameters and carcinogenicity have been well documented. Treatment of male Wistar rats for five consecutive days with 2-AAF i.p. induced significant hepatic toxicity, oxidative stress and hyperproliferation. Pretreatment of T. gallica extract (25 and 50 mg/kg body wt.) prevented oxidative stress by restoring the levels of antioxidant enzymes and also prevented toxicity at both the doses. The promotion parameters induced (ornithine decarboxylase activity and DNA synthesis) by 2-AAF administration in diet with partial hepatectomy (PH) were also significantly suppressed dose-dependently by T. gallica. Therefore, we can conclude that ultimately the protection against liver carcinogenesis by T. gallica methanolic extract might be mediated by multiple actions, which include restoration of cellular antioxidant enzymes, detoxifying enzymes, ODC activity and DNA synthesis.
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PMID:Evaluation of possible mechanisms of protective role of Tamarix gallica against DEN initiated and 2-AAF promoted hepatocarcinogenesis in male Wistar rats. 1669 44

Recent advances in our knowledge of arsenic carcinogenesis include the development of rat or mouse models for all human organs in which inorganic arsenic is known to cause cancer- skin, lung, urinary bladder, liver, and kidney. Tumors can be produced from either promotion of carcinogenesis protocols or from complete carcinogenesis protocols. Experiments with p53 + / - and K6/ODC transgenic mice administered dimethylarsinic acid (DMA) or arsenite have shown some degree of carcinogenic, cocarcinogenic, or promotional activity in skin or bladder. At present, with the possible exception of skin, the arsenic carcinogenesis models in wild-type animals are more highly developed than in transgenic mice. In this review, animal models of arsenic carcinogenesis are presented and discussed animal models of DMA carcinogenesis, transgenic animal models of arsenic carcinogenesis, and methylated metabolites of arsenic.
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PMID:[Current progress in animal models of arsenic carcinogenesis]. 1729 Jul 76

The activity of ornithine decarboxylase (ODC(1)), the first enzyme in polyamine biosynthesis, is induced during carcinogenesis by a variety of oncogenic stimuli. Intracellular levels of ODC and the polyamines are tightly controlled during normal cell growth, and regulation occurs at the levels of transcription, translation and protein degradation. Several known proto-oncogenic pathways appear to control ODC transcription and translation, and dysregulation of pathways downstream of ras and myc result in the constitutive elevation of ODC activity that occurs with oncogenesis. Inhibition of ODC activity reverts the transformation of cells in vitro and reduces tumor growth in several animal models, suggesting high levels of ODC are necessary for the maintenance of the transformed phenotype. The ODC irreversible inactivator DFMO has proven to be not only a valuable tool in the study of ODC in cancer, but also shows promise as a chemopreventive and chemotherapeutic agent in certain types of malignancies.
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PMID:Regulation of ornithine decarboxylase during oncogenic transformation: mechanisms and therapeutic potential. 1744 68


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