8-hydroxy-2--deoxyguanosine and Esophageal-Neoplasms

Barrett's esophagus (BE), a chronic inflammatory condition, is the leading risk factor for esophageal adenocarcinoma (EAC). In inflammation to cancer pathways, oxidative stress profiles have been linked to cancer progression. However, the relevance of oxidative stress profiles along the BE-disease sequence remains to be elucidated. In this study, markers of oxidative stress; DNA adducts (8-oxo-dG) and lipoperoxidation (4-HNE), and markers of proliferation (Ki67) were measured in patient biopsies representing the BE-disease sequence. Differences in expression of these markers in Barrett's patients with cancer-progression and non-progression were examined. Proliferation was reduced in Barrett's specialized intestinal metaplasia (SIM) compared with EAC (

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Aldehydes; Apoptosis; Barrett Esophagus; Cell Proliferation; Esophageal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Oxidative Stress; Transcriptome

MutT homolog-1 (MTH1) is a pyrophosphatase that acts on oxidized nucleotides and hydrolyzes 8-oxo-2'-deoxyguanosine triphosphate in deoxynucleoside triphosphate pool to prevent its incorporation into nuclear and mitochondrial DNA, result in reduce cytotoxicity in tumor cells. MTH1 is overexpressed in various cancers and is considered as a therapeutic target. Environmental factors such as cigarette smoking and alcohol consumption are critical risk factors for the development and progression of esophageal squamous cell carcinoma (ESCC), suggesting that oxidative stress contributes to the pathogenesis of ESCC. We examined the expression of MTH1 and the accumulation of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in 84 patients with ESCC who underwent curative resection without neoadjuvant therapy. MTH1 mRNA level was quantified by performing quantitative reverse transcription-PCR. Immunohistochemical analysis of paraffin-embedded cancer tissues was performed to determine MTH1 protein expression and 8-oxo-dG accumulation. MTH1 mRNA expression was higher in cancerous tissues than in the corresponding normal epithelium (P < 0.0001). Immunohistochemical analysis showed that high MTH1 expression was significantly associated with deeper tumor invasion and venous invasion, advanced cancer stage, and poor overall survival (P = 0.0021) and disease-specific survival (P = 0.0013) compared with low MTH1 expression. Furthermore, high MTH1 expression was an independent predictor of poor disease-specific survival (P = 0.0121). In contrast, 8-oxo-dG accumulation was not associated with any clinicopathological factor and poor prognosis. These results suggest that MTH1 overexpression is a predictor of ESCC progression and poor prognosis and that MTH1 can serve as a therapeutic target for treating patients with ESCC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Carcinoma, Squamous Cell; Cell Line, Tumor; Deoxyguanosine; DNA Repair Enzymes; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Male; Middle Aged; Neoplasm Invasiveness; Phosphoric Monoester Hydrolases; Prognosis; Survival Analysis; Treatment Outcome; Up-Regulation

Chronic inflammation is associated with increased risk of cancer development, whereas the link between chronic inflammation and esophageal carcinogenesis is still obscure heretofore. This study aimed to investigate the relationship between chronic inflammation and DNA damage, as well as the possible role of DNA damage in esophageal carcinogenic process. Endoscopic esophageal biopsies from 109 individuals from Chaoshan littoral, a high-risk region for esophageal squamous cell carcinoma (ESCC), were examined to evaluate the association between chronic inflammation and histological severity, while additional 204 esophageal non-tumor samples from patients with ESCC were collected. Immunohistochemistry was performed to detect the oxidative DNA damage and DNA double-strand breaks (DSBs). Significantly positive correlation was observed between degree of chronic inflammation and esophageal precursor lesions (rs = 0.37, P < 0.01). Immunohistochemical analysis showed that oxidative DNA damage level was positively correlated with the degree of chronic inflammation (rs = 0.21, P < 0.05). Moreover, the level of oxidative DNA damage positively correlated with histological severity (rs = 0.49, P < 0.01). We found that the extent of DSBs was progressively increased with inflammation degree (P < 0.01) and the progression of precancerous lesions (P < 0.001). Collectively, these findings provide evidence linking chronic inflammation-associated genomic instability with esophageal carcinogenesis and suggest possibilities for early detection and intervention of esophageal carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Carcinogenesis; Carcinoma, Squamous Cell; Chronic Disease; Deoxyguanosine; Disease Progression; DNA Damage; Esophageal Neoplasms; Esophagus; Female; Genomic Instability; Histones; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged

Barrett's esophagus (BE) caused by gastroesophageal reflux is a major risk factor of Barrett's esophageal adenocarcinoma (BEA), an inflammation-related cancer. Chronic inflammation and following tissue damage may activate progenitor cells under reactive oxygen/nitrogen species-rich environment. We previously reported the formation of oxidative/nitrative stress-mediated mutagenic DNA lesions, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-nitroguanine, in columnar epithelial cells of BE tissues and cancer cells of BEA tissues. We investigated the mechanisms of BEA development in relation to oxidative/nitrative DNA damage and stem cell hypothesis. We examined 8-nitroguanine and 8-oxodG formation and the expression of stem cell marker (CD133) in biopsy specimens of patients with BE and BEA by immunohistochemical analysis in comparison with those of normal subjects. CD133 was detected at apical surface of columnar epithelial cells of BE and BEA tissues, and the cytoplasm and cell membrane of cancer cells in BEA tissues. DNA lesions and CD133 were colocalized in columnar epithelial cells and cancer cells. Their relative staining intensities in these tissues were significantly higher than those in normal subjects. Our results suggest that BE columnar epithelial cells with CD133 expression in apical surface undergo inflammation-mediated DNA damage, and mutated cells acquire the property of cancer stem cells with cytoplasmic CD133 expression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; AC133 Antigen; Adenocarcinoma; Aged; Barrett Esophagus; Deoxyguanosine; DNA Damage; Epithelial Cells; Esophageal Neoplasms; Esophagus; Female; Humans; In Vitro Techniques; Male; Middle Aged; Oxidative Stress; Reactive Oxygen Species

Both internal and external oxidative stresses act on DNA and can induce carcinogenesis. 8-hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and it leads to transversion mutations and carcinogenesis. 8-OHdG is excision-repaired by 8-OHdG DNA glycosylase (OGG1). The purpose of this study is to clarify the effect of oxidative DNA damage and repair enzymes on esophageal carcinogenesis. The levels of 8-OHdG and OGG1 were immunohistochemically evaluated in resected specimens, including squamous cell carcinoma (SCC) in 97 patients with esophageal cancer. Higher levels of 8-OHdG in normal esophageal epithelium were associated with a higher smoking index (P = 0.0464). The 8-OHdG level was higher in cancerous areas than in normal epithelia (P = 0.0061), whereas OGG1 expression was weaker in cancerous areas than in normal epithelia (P < 0.0001). An increase of OGG1 expression in normal epithelium was observed as 8-OHdG levels increased (P = 0.0011). However, this correlation was not observed in cancerous areas. High OGG1 expression in the cytoplasm was related to deeper tumors (P = 0.0023), node metastasis (P = 0.0065) and stage (P = 0.0019). Oxidative DNA damage, which is attributable to smoking as well as disturbances in DNA repair systems, appears to be closely related to esophageal carcinogenesis and its progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Carcinoma, Squamous Cell; Deoxyguanosine; DNA Damage; DNA Glycosylases; DNA Repair Enzymes; Epithelium; Esophageal Neoplasms; Esophagus; Female; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Oxidative Stress; Smoking

Esophageal cancer is characterized by increased oxidative stress and the production of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is one of the main mutagenic modifications of DNA. We analyzed the predictive value of 8-OHdG expression on postoperative survival of patients with esophageal cancer with univariate and multivariate analysis. The high levels of 8-OHdG are associated with significantly shorter survival time by log-rank test using Kaplan-Meier methods. Moreover, the level of 8-OHdG expression was identified as an independent predictor for esophageal cancer outcome using Cox proportional hazards model analysis (relative risk, 0.294; 95% confidence interval, 0.178-0.487; P = .000). These results suggest that oxidative damage marker of 8-OHdG is a useful prognostic marker in esophageal cancer. The analysis of 8-OHdG levels can help in the identification of patient subgroups that are at high risk for poor disease outcomes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Carcinoma, Squamous Cell; China; Deoxyguanosine; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Postoperative Period; Survival Analysis; Treatment Outcome

The present report was designed to investigate the origins of elevated oxidative stress measured in cancer patients in our previous work related to a case-control study (17 cases, 43 controls) on oesophageal cancers. The aim was to characterize the relationship between the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), antioxidant vitamins and genetic susceptibility.. 8-oxodG was analysed in peripheral blood mononuclear cells (PBMCs) by High Performance Liquid Chromatography with Electrochemical Detection (HPLC-ED). Analysis of gene polymorphisms in GSTM1 and GSTT1 was performed by multiplex PCR and in GSTP1 and hOGG1 by a PCR-RFLP method. Reversed-phase HPLC with UV detection at 294 nm was used to measure vitamins A and E in serum from the same blood samples.. We observed that in our combined population (cases and control, n = 60), there was no statistically significant correlation between the levels of 8-oxodG and (i) the serum concentration of antioxidant vitamins, vitamin A (P = 0.290) or vitamin E (P = 0.813), or (ii) the incidence of the Ser326Cys polymorphic variant (P = 0.637) of the hOGG1 gene. Also, the levels of 8-oxodG were not significantly associated with polymorphisms in metabolite-detoxifying genes, such as GSTs, except for the positive correlation with Val/Val GST P1 allele (P < 0.0001).. The weakness of our cohort size notwithstanding, vitamins levels in serum and genetic polymorphisms in the hOGG1 or GST genes do not appear to be important modulators of 8-oxodG levels.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Biomarkers, Tumor; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA Glycosylases; Esophageal Neoplasms; Genetic Predisposition to Disease; Glutathione Synthase; Humans; Oxidative Stress; Polymorphism, Single Nucleotide; Vitamins

Evaluation of oxidative stress and diagnostic utility of its markers in oesophageal squamous cell carcinoma (OSCC).. Serum 8-hydroxydeoxyguanosine, thiobarbituric acid-reactive substances (TBARS) and total antioxidant status (TAS) were measured in OSCC (n=75), non-malignant oesophageal diseases (n=30), and healthy subjects (n=79). Three months following oesophagectomy the measurements were repeated.. Exclusively in OSCC, 8-hydroxydeoxyguanosine and TBARS were elevated. TAS was reduced in non-malignancies compared to controls, and in OSCC compared to non-malignancies and controls. Only 8-hydroxydeoxyguanosine was associated with disease progression, lymph node involvement in particular. All indices were good indicators of cancer presence (ROC analysis) and normalized following oesophagectomy. A positive linear relationship between 8-hydroxydeoxyguanosine and TBARS, and negative non-linear between TAS and both 8-hydroxydeoxyguanosine and TBARS was demonstrated.. OSCC is associated with oxidative stress, attenuated following oesophagectomy. Consumption of serum antioxidants prevents accumulation of oxidatively modified molecules in non-malignancies. High accuracy of oxidative stress markers in indicating cancer presence warrants further investigation on their possible application as discriminatory markers and in monitoring treatment efficacy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Biomarkers; Biomarkers, Tumor; Carcinoma, Squamous Cell; Deoxyguanosine; Diagnosis, Differential; Esophageal Diseases; Esophageal Neoplasms; Humans; Lymphatic Metastasis; Neoplasm Staging; Oxidative Stress; Radiography; Thiobarbituric Acid Reactive Substances

The most common marker of oxidative DNA damage is 8-hydroxydeoxyguanosine (8-OHdG), which is linked with several malignancies. In the present study we investigated whether DNA damage linked to oxidative stress (as 8-OHdG) is present in Barrett's mucosa with or without associated adenocarcinoma or high-grade dysplasia and in normal controls' squamous mucosa.. We measured 8-OHdG in 51 patients (13 Barrett's metaplasia, six Barrett's oesophagus with high-grade dysplasia, 18 adenocarcinoma of the distal oesophagus/oesophagogastric junction and 14 normal controls). The amount of DNA damage was determined by high-performance liquid chromatography in oesophagus samples obtained either from endoscopy or as samples from surgery. The median 8-OHdG concentration was expressed as the ratio of 8-OHdG per 10(5) deoxyguanosine.. Analysis revealed that 8-OHdG was present in both Barrett's metaplasia with and without dysplasia as well as in adenocarcinoma of the oesophagus/oesophagogastric junction. Although the study group was small the amount of 8-OHdG was significantly increased in the distal oesophagus both in Barrett's epithelium 1.26 (0.08-29.47) and in high-grade dysplasia 1.35 (1.04-1.65) as well as in adenocarcinoma of oesophagus/oesophagogastric junction 1.08 (0.59-1.94) compared to controls 0.06 (0-4.08) (p=0.002, p=0.012, p=0.001, respectively). Barrett's patients had no significant difference in 8-OHdG levels between their distal and proximal oesophageal samples.. Our results show the presence of oxidative DNA damage in the distal oesophagus of patients with Barrett's oesophagus and adenocarcinoma of the oesophagus/oesophagogastric junction. This may have a connection to carcinogenesis in Barrett's oesophagus.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Biopsy; Deoxyguanosine; DNA Damage; Esophageal Neoplasms; Esophagogastric Junction; Esophagoscopy; Esophagus; Female; Humans; Male; Middle Aged; Mucous Membrane; Oxidative Stress

Comprehensive understanding of the basic mechanisms in the progression of esophagitis, Barrett esophagus (BE), and esophageal adenocarcinoma (EAC) is urgently needed to develop a management strategy for an effective screening of BE and management of EAC. The aim of this study is to provide a detailed insight of the histology and the cellular and molecular events associated with the genesis of BE and EAC under the esophagoduodenal reflux conditions.. Esophagoduodenal anastomosis (EDA) was performed on rats. Animals were weighed weekly and killed after 1, 2, 3, 4, 5, and 6 months. The entire esophagi were examined for macroscopic and microscopic changes and for manganese superoxide dismutase (MnSOD) expression, and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assay was performed.. Morphological transformation from esophagitis (100% of animals) to BE (66% of animals) to EAC was observed after 3 months. There was marked loss of MnSOD expression in animals with esophagitis and BE at 1 and 2 months, with an increase in expression during the transformation to dysplasia and EAC. Increased proliferation and apoptosis was observed and reached a peak at months 1 and 2. Greatly increased levels of 8-hydroxy-deoxyguanosine was found during the progression to EAC.. The morphological transformation of the esophageal mucosa is an adaptive process, and it is an important foundation for the transdifferentiation of BE and cancer. The significant loss of MnSOD expression to achieve BE and then the adaptive increase in expression to achieve dysplasia and EAC during this transformation may represent a predictive marker in identifying patients who will progress from BE to EAC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Anastomosis, Surgical; Animals; Apoptosis; Barrett Esophagus; Cell Proliferation; Deoxyguanosine; Disease Models, Animal; Disease Progression; Duodenum; Epithelial Cells; Esophageal Neoplasms; Esophagitis, Peptic; Esophagus; Immunohistochemistry; Oxidative Stress; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Oxidative stress is related to the carcinogenic pathway of reflux esophagitis to Barrett's metaplasia to esophageal adenocarcinoma (EAC). Recent studies have shown that a decreased manganese superoxide dismutase (MnSOD) level is associated with the increased incidences of Barrett's esophagus (BE) and EAC. The aim of this study was to investigate MnSOD supplementation as a chemopreventive agent to prevent oxidative injury and subsequent BE and EAC formation.. Our esophagoduodenal anastomotic (EDA) model was done on rats according to our established procedure and treated with Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP; 10 mg/kg, i.p. every 3 days). Histologic changes were determined after the EDA model at 1, 3, and 6 months. Lipid peroxidation and 8-hydroxy-deoxyguanosine for DNA oxidative damage were determined by thiobarbituric acid-reactive substance assay and immunohistochemical staining. Enzymatic activities of MnSOD and Cu/ZnSOD were evaluated, and the rate of proliferation was determined by proliferating cell nuclear antigen staining.. Severe esophagitis was seen in 100% of the EDA rats, and morphologic transformation within the esophageal epithelium was observed with intestinal metaplasia (40% of animals) and cancer (40% of animals) identified after 3 months. Decreased oxidative damage, along with the decreased degree of esophagitis and incidence of BE (20%) and EAC (0%), was found in MnTBAP-treated EDA rats comparing with the saline-treated EDA control. Decreased proliferation (46%) and increased SOD enzymatic activities (25%) were also found in the EDA rats treated with MnTBAP.. MnTBAP protected rat esophageal epithelium from oxidative injury induced by EDA, and it could prevent the transformation of esophageal epithelial cell to BE to EAC by preservation of antioxidants.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Animals; Anticarcinogenic Agents; Antioxidants; Apoptosis; Cell Proliferation; Deoxyguanosine; Esophageal Neoplasms; Esophagus; Metalloporphyrins; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Oxidative stress is connected with activation of somatic mutations and rates of cell proliferation existing in cancer tissue. High level of reactive oxygen species is a mutagenic factor for DNA damage. Antioxidants are the components of the cellular defense mechanism against reactive oxygen molecules. The aim of our study was to analyze DNA peroxidation products' concentration and total antioxidant level in serum of the patients with esophageal squamous cell carcinoma before and after esophagectomy. We examined these parameters as markers of cancer development.. We tested 18 patients (2 woman and 16 men, mean age 59.4 years) with esophageal squamous cell cancer before and after esophagectomy and 12 healthy people as a control group. Concentrations of 8-OHdG and enzymatic antioxidants level were analyzed in serum. Data were statistically analyzed by Mann-Whitney test.. We observed statistically significant higher concentrations of 8-OHdG and significant lower levels of enzymatic antioxidants in the patients with cancer in comparison to the control group. After esophagectomy we observed normalization of these parameters. In four patients the level of total antioxidants was low and 8-OHdG concentration was high during the whole time of treatment. These patients had disease progression.. Estimation of serum 8-OHdG concentration and total antioxidant status may be helpful for monitoring cancer therapy in patients with esophageal squamous cell cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antioxidants; Carcinoma, Squamous Cell; Deoxyguanosine; DNA Damage; Esophageal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Models, Biological; Mutation; Reactive Oxygen Species; Treatment Outcome

Increased fruit and vegetable consumption is associated with decreased risk of a number of cancers of epithelial origin, including esophageal cancer. Dietary administration of lyophilized black raspberries (LBRs) has significantly inhibited chemically induced oral, esophageal, and colon carcinogenesis in animal models. Likewise, berry extracts added to cell cultures significantly inhibited cancer-associated processes. Positive results in preclinical studies have supported further investigation of berries and berry extracts in high-risk human cohorts, including patients with existing premalignancy or patients at risk for cancer recurrence. We are currently conducting a 6-mo chemopreventive pilot study administering 32 or 45 g (female and male, respectively) of LBRs to patients with Barrett's esophagus (BE), a premalignant esophageal condition in which the normal stratified squamous epithelium changes to a metaplastic columnar-lined epithelium. BE's importance lies in the fact that it confers a 30- to 40-fold increased risk for the development of esophageal adenocarcinoma, a rapidly increasing and extremely deadly malignancy. This is a report on interim findings from 10 patients. To date, the results support that daily consumption of LBRs promotes reductions in the urinary excretion of two markers of oxidative stress, 8-epi-prostaglandin F2alpha (8-Iso-PGF2) and, to a lesser more-variable extent, 8-hydroxy-2'-deoxyguanosine (8-OHdG), among patients with BE.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Anticarcinogenic Agents; Barrett Esophagus; Biomarkers; Deoxyguanosine; Dinoprost; Esophageal Neoplasms; Female; Food Preservation; Freeze Drying; Fruit; Gastroesophageal Reflux; Humans; Male; Middle Aged; Oxidative Stress; Phytotherapy; Pilot Projects; Precancerous Conditions; Rosaceae

8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is a widely used biomarker to evaluate the level of oxidative stress. This study describes in its first part the optimisation of our analytical procedure (HPLC/electrochemical detection). Particular care was exercised to avoid artefactual oxidation and in the precision of measurement, which was evaluated with blood bags from hemochromatosis patients. The best results were obtained with a DNA extraction step using the "chaotropic method" recommended by the European Standards Committee on Oxidative DNA Damage (ESCODD). Other approaches such as anion exchange columns gave ten times as much 8-oxodG as this method. Moreover, a complete DNA hydrolysis using five different enzymes allowed improved precision. The optimised protocol was applied to peripheral blood mononuclear cells (PBMC) sampled during a case-control study on cancers of the oesophagus and cardia. With 7.2 +/- 2.6 8-oxodG/10(6) 2'-deoxyguanosines (2'-dG) (mean +/- SD), patients (n = 17) showed higher levels of 8-oxodG than controls (4.9 +/- 1.9 8-oxodG/10(6) 2'-dG, n = 43, Student's t-test: p < 0.001). This difference remained significant after technical (storage, sampling period, 2'-dG levels) and individual (age, sex, smoking, alcohol) confounding factors were taken into account (p < 0.0001, Generalised Linear regression Model). To our knowledge, this is the first report to demonstrate an increase of 8-oxodG in PBMCs of patients suffering from a cancer of the upper digestive tract. This elevated level of DNA damage in patients can raise interesting issues: is oxidative stress the cause or the result of the pathology? Could this biomarker be used to evaluate chemoprevention trials concerning digestive tract cancers?

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA; DNA Damage; Electrochemistry; Esophageal Neoplasms; Female; Humans; Hydrolysis; Leukocytes, Mononuclear; Linear Models; Male; Middle Aged; Models, Chemical; Oxidative Stress; Oxygen; Stomach Neoplasms; Time Factors

Oxidative damage has long been related to carcinogenesis in human cancers and animal cancer models. Recently a rat esophageal adenocarcinoma (EAC) model was established in our laboratory by using esophagoduodenal anastomosis (EDA) plus iron supplementation. Our previous study suggested that iron supplementation enhanced inflammation and the production of reactive nitrogen species in the esophageal epithelium, which could contribute to esophageal adenocarcinogenesis. Here we further characterized oxidative damage in this model. We were particularly interested in how excess iron was deposited in the esophagus, and which cells were targeted by oxidative damage. Male Sprague-Dawley rats received iron supplementation (50 mg Fe/kg/month, i.p.) starting 4 weeks after EDA. The animals were killed at 11, 30 or 35 weeks after surgery. EAC appeared as early as week 11 after surgery, and increased over time, up to 60% at 35 weeks after surgery. All EACs were well-differentiated mucinous adenocarcinoma at the squamocolumnar junction. Iron deposition was found at the squamocolumnar junction and in the area with esophagitis. Esophageal iron overload could result from transient increase of blood iron after i.p. injection, and the overexpression of transferrin receptor in the premalignant columnar-lined esophagus (CLE) cells. Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine), protein (carbonyl content) and lipid (thiobarbituric acid reactive substance) in the esophagus was significantly higher than that of the non-operated control. CLE cells were believed to be the target cells of oxidative damage because they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. We propose that oxidative damage plays an important role in the formation of EAC in the EDA model, and a similar situation may occur in humans with gastroesophageal reflux and iron over-nutrition.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma, Mucinous; Anastomosis, Surgical; Animals; Barrett Esophagus; Cocarcinogenesis; Deoxyguanosine; Disease Models, Animal; DNA Adducts; Duodenum; Epithelial Cells; Esophageal Neoplasms; Esophagitis; Esophagus; Gastroesophageal Reflux; Heme Oxygenase (Decyclizing); Humans; Iron; Isoenzymes; Male; Metallothionein; Oxidative Stress; Postoperative Complications; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Transferrin; Thiobarbituric Acid Reactive Substances