8-hydroxy-2--deoxyguanosine and Adenocarcinoma

As part of a randomized placebo-controlled study to evaluate the effect of lycopene supplementation on DNA damage in men with prostate cancer, a nonrandomized 5th arm using tomato sauce was included and reported here. Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for 3 weeks (30 mg of lycopene/day) before their scheduled radical prostatectomy. Prostate tissue was obtained as biopsies at baseline and as resected tissue at the time of the prostatectomy. Serum and prostate lycopene, serum prostate specific antigen (PSA) concentrations, and leukocyte DNA 8-OH-deoxyguanosine/deoxyguanosine (8OHdG) were measured at baseline and at the end of the intervention. Cancer cells in paraffin sections of prostate biopsies and postintervention resected tissue were compared for 8OHdG staining and for apoptosis. Adherence to the daily consumption of tomato-based entrees was 81.6% of the intended dose, and serum and prostate lycopene concentrations increased 1.97- and 2.92-fold (P < 0.001), respectively. Mean serum PSA concentrations decreased by 17.5% (P < 0.002) and leukocyte 8OHdG decreased by 21.3% (P < 0.005) after tomato sauce consumption. Resected tissues from tomato sauce-supplemented patients had 28.3% lower prostate 8OHdG compared with the nonstudy control group (P < 0.03). Cancer cell 8OHdG staining of Gleason Score-matched resected prostate sections was reduced by 40.5% in mean nuclear density (P < 0.005) and by 36.4% in mean area (P < 0.018) compared with the presupplementation biopsy. Apoptotic index was higher in hyperplastic and neoplastic cells in the resected tissue after supplementation. These data taken as a whole indicate significant uptake of lycopene into prostate tissue and a reduction in DNA damage in both leukocyte and prostate tissue. Whether reduction in DNA damage to prostate cancer cells is beneficial awaits further research, although reduction in serum PSA concentrations is promising.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Anticarcinogenic Agents; Antioxidants; Apoptosis; Carotenoids; Deoxyguanosine; Humans; Lycopene; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Solanum lycopersicum

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

The effects of oxidative stress in adenocarcinomas of gastric cardia (AGCs) have not been fully elucidated. With a strict definition of AGC, we examined the immunohistochemical expressions of inducible nitric oxide synthase; 8-hydroxy-deoxyguanosine; and the base excision repair enzymes such as MUTYH, MTH1, and OGG1, and TP53 mutational status. Sixty-three cases of AGC were characterized by younger patient age (P = .0227) and more frequent venous invasion (P = .0106) compared with the adenocarcinomas of pylorus (APs). 8-hydroxy-deoxyguanosine was accumulated (P = .0011), whereas MUTYH (P = .0325) and OGG1 (P = .0007) were decreased, in the AGCs compared with the adjacent mucosa, but these differences were not detected in the APs. Among the AGCs, lower expressions of MUTYH (P = .0013) and MTH1 (P = .0059) were each significantly associated with diffuse-type histology. A lower expression of OGG1 was correlated with higher T-stage (P = .0011), lymphatic invasion (P = .004), and lymph node metastasis (P = .0094). In addition, the presence of TP53 mutation was associated with diffuse-type histology (P = .0153) and a lower level of MUTYH (P = .0221). The AGCs also showed a relatively high rate of a transversion-type mutation of TP53 (50%), whereas all TP53 mutations in the APs were transition type. Age 62years or older (P = .0073), diffuse-type histology (P = .0020), and TP53 mutation (P = .0066) were each associated with worse survival in the AGC patients. Our results indicate that oxidative stress accumulation and a downregulation of base excision repair enzymes may play an important role in the pathogenesis of AGC, in particular diffuse-type AGCs. Diffuse-type AGC might involve molecular pathways different from those of other subsets of gastric cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cardia; Deoxyguanosine; Disease-Free Survival; DNA Glycosylases; DNA Mutational Analysis; DNA Repair; DNA Repair Enzymes; Down-Regulation; Female; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Mutation; Neoplasm Staging; Nitric Oxide Synthase Type II; Oxidative Stress; Phenotype; Phosphoric Monoester Hydrolases; Retrospective Studies; Stomach Neoplasms; Tumor Suppressor Protein p53

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

Oxidative stress and redox-regulating enzymes may potentially accelerate pancreatic carcinogenesis and also affect chemoresistance. Recently major antioxidant response regulator NF-E2-related factor 2 (Nrf2) has been linked to poor prognosis in pancreatic cancer. Nrf2 activity is strictly regulated by oxidative stress sensor Kelch-like ECH-associated protein 1 (Keap1). Oxidative DNA damage can be estimated e.g. by 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression. The aim of this study was to evaluate the expression and possible prognostic role of Keap1 and 8-OHdG in pancreatic cancer.. We assessed immunohistochemically the expression of 8-OHdG and Keap1 in precisely characterized material of 69 pancreatic adenocarcinoma patients.. Nuclear 8-OHdG associated with cytoplasmic Keap1 expression (p = 0.031) and was overexpressed in patients with smaller tumors (p = 0.016) and in tumors without lymph node involvement (p = 0.051). Cytoplasmic 8-OHdG expression associated with higher differentiation (p = 0.023). Cytoplasmic Keap1 immunostaining associated with N0-staging (p = 0.0009) and the absence of distant metastases (p = 0.018). Membranous Keap1 associated with longer relapse-free survival (p = 0.041) and pancreatic cancer-specific survival (median survival 14 vs. 32 months; p = 0.029) and was in multivariate analysis an independent prognostic factor of pancreatic cancer-related death (HR 2.66, 95%CI 1.23-5.75).. Oxidative stress and main redox regulators may participate in pancreatic carcinogenesis and Keap1 appears as a promising prognostic factor in pancreatic cancer. Future studies should also concentrate on potential link between redox regulation and chemoresistance in pancreatic cancer.. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4220521801406476.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Biomarkers, Tumor; Cause of Death; Cell Differentiation; Chi-Square Distribution; Deoxyguanosine; Disease-Free Survival; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Kelch-Like ECH-Associated Protein 1; Lymphatic Metastasis; Multivariate Analysis; Oxidation-Reduction; Oxidative Stress; Pancreatic Neoplasms; Proportional Hazards Models; Risk Factors; Time Factors; Treatment Outcome; Tumor Burden

Cancers have dysfunctional redox regulation resulting in production of reactive oxygen species (ROS), damaging DNA, RNA and free NTPs, and causing the accumulation of oxidative nucleic acids in cytoplasm. The major types are 8-oxo-7,8-dihydroguanine(8-oxoGsn) in RNA and 8-oxo-7,8-dihydro-2' deoxyguanosine(8-oxodGsn) in Mt-DNA. The MTH1 protein sanitizes oxidized nucleotide pools from NTPs to monophosphates, preventing the occurrence of transversion mutations. This study concerned cytoplasmic 8-oxodGsn/Gsn and MTH1 expression in gastric cancer and para-cancer tissues and elucidated roles of nucleic-acid oxidation and anti-oxidation.. A polymer HRP detection system was used to detect 8-oxo-Gsn/dGsn and MTH1 expression in 51 gastric cancer and para-cancer tissue samples. Analyses of patient clinical and pathological data were also performed.. The expression of MTH1 and the 8-oxo-dGsn/Gsn ratio were significantly higher in cancer tissues than para-cancer tissues (P<0.05). Cytoplasmic 8-oxo-Gsn and MTH1 were both found to positively correlate (P<0.05) with tumor differentiation, while no significant associations were found with gender, age, invasion depth, lymph node metastasis and clinical stage (P>0.05).. We found 8-oxo-dGsn/Gsn and MTH1 are both highly expressed in gastric cancer tissues, especially in well differentiated lesions. In addition, oxidated mtDNA is prevalently expressed in gastric cancers, while 8-oxo-Gsn expression in cytoplasmic RNA is a bit lower, but more selectively.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Cytoplasm; Deoxyguanosine; DNA Repair Enzymes; Female; Guanine; Humans; Male; Middle Aged; Mitochondria; Neoplasm Grading; Phosphoric Monoester Hydrolases; Stomach; Stomach Neoplasms

The aim of this work was to answer the question whether the broad range of parameters which describe oxidative stress and oxidatively damaged DNA and repair are appropriate prognosis factors of colon cancer (CRC) patients survival? The following parameters were analyzed for 89 CRC patients: concentration of uric acid and vitamins A, E, C in plasma; levels of 8-oxodGuo (8-oxo-7,8-dihydro-2'-deoxyguanosine) in DNA of leukocyte and colon tissues; urinary excretion rates of 8-oxodGuo and 8-oxoGua (8-oxo-7,8-dihydroguanine); the activity and mRNA or protein level of repair enzymes OGG1, APE1, ANPG, TDG and PARP1. All DNA modifications and plasma antioxidants were analyzed using high performance liquid chromatography (HPLC) or HPLC/gas chromatography-mass spectrometry techniques. Expression of repair proteins was analyzed by QPCR, Western or immunohistochemistry methods. Longer survival coincided with low levels of 8-oxodGuo/8oxoGua in urine and 8-oxodGuo in DNA as well as with high concentration of uric acid plasma level. In contrast to expectations, longer survival coincided with lower mRNA level in normal colon tissue of the main 8-oxoGua DNA glycosylase, OGG1, but no association was found for PARP-1 expression. When analyzing simultaneously two parameters the discriminating power increased significantly. Combination of low level of urinary 8-oxoGua together with low level of 8-oxodGuo in leukocyte (both below median value) or high concentration of plasma uric acid (above median value) have the best prediction power. Since prediction value of these parameters seems to be comparable to conventional staging procedure, they could possibly be used as markers to predict clinical success in CRC treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Chromatography, High Pressure Liquid; Colonic Neoplasms; Deoxyguanosine; DNA Damage; DNA Repair Enzymes; Female; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Guanine; Humans; Male; Middle Aged; Neoplasm Staging; Oxidative Stress; Prognosis; Survival Rate; Uric Acid

Oxidative stress is a contributing factor in the carcinogenesis of colorectal cancer. The Nrf2 [nuclear factor (erythroid-derived 2)-like 2; NFE2L2] pathway is one of the major cellular defense mechanisms against oxidative stress. This study investigated the expression of the Nrf2 pathway in colorectal cancer. Formalin-fixed paraffin-embedded tissue arrays consisting of the tumor, adjacent normal, and distant normal tissues from the resected specimens of 83 colorectal cancer patients were subjected to immunohistochemical (IHC) staining with antibodies against Nrf2, kelch-like ECH-associated protein 1 (Keap1), p21, P62, Parkinson protein 7 (Park7), prohibitin, BTB and CNC homology 1 (Bach1), CD34 and 8-hydroxy-2'-deoxyguanosine (8-OHdG). The mean IHC density of each IHC staining was digitally analyzed. The results showed that molecules of the Nrf2 pathway were actively expressed, with different expression profiles among the tumor and normal tissues. The oxidative stress, represented by the mean IHC staining density of 8-OHdG, did not differ but was correlated with the expressions of different Nrf2 pathway molecules to a varied extent in tumor and normal tissues of colorectal cancer. Keap1 [estimate, 0.49; 95% confidence interval (CI), 0.19-0.79] and Bach1 (estimate, 0.24; 95% CI, 0.11-0.38) were significant predictors for the expression of 8-OHdG and had the closest proximity to Nrf2 in the cluster dendrogram of the tumor and distant normal tissues, respectively. Advanced stage (estimate, 14.9; 95% CI, 2.99-26.8) and current smoker (estimate, 15.6; 95% CI, 1.92-29.3) were significant predictors with high estimates for Bach1 in the adjacent and distant normal tissues, respectively. In colorectal cancer, the molecules of the Nrf2 pathway have different expression profiles and a difference in their importance, especially Keap1 and Bach1, related to Nrf2 and oxidative stress among tumor and normal tissues.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Aged; Aged, 80 and over; Basic-Leucine Zipper Transcription Factors; Colorectal Neoplasms; Deoxyguanosine; Fanconi Anemia Complementation Group Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; Male; Middle Aged; Neoplasm Staging; NF-E2-Related Factor 2; Oxidative Stress; Risk Factors; Signal Transduction; Smoking

In the case of carcinogenesis in human endometrium no information exists on tissue concentration of 8-oxo-7,8-dihydroguanine, the DNA oxidative stress marker This was the main reason to undertake the investigation of this DNA modification in human uterine estrogen-dependent tissue cancers.. In order to estimate the level of oxidative damage, 8-oxo-7,8-dihydroguanine was determined directly in cells of tissue microscope slides using OxyDNA Assay Kit, Fluorometric. Cells were investigated under confocal microscope. Images of individual cells were captured by computer-interfaced digital photography and analyzed for fluorescence intensities (continuous inverted 8-bit gray-scale = 0 [black]-255 [white]). Fluorescence scores were calculated for each of 13 normal endometrial samples and 31 uterine adenocarcinoma specimens. Finally the level of the oxidative stress marker was also analyzed according to histological and clinical features of the neoplasms.. The obtained data revealed that: 8-oxo-7,8-dihydroguanine levels were higher in uterine adenocarcinomas than in normal endometrial samples (48,32 vs. 38,64; p<0,001); in contrast to normal endometrium there was no correlation between age and DNA oxidative modification content in uterine cancer; highest mean fluorescence intensity was recognized in G2 endometrial adenocarcinomas; level of 8-oxo-7,8-dihydroguanine does not depend on Body Mass Index (BMI) and cancer uterine wall infiltration or tumor FIGO stage.. Our study indicates that accumulation of the oxidized DNA base may contribute to the development of endometrial neoplasia, however oxidative DNA damage does not seem to increase with tumor progression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; DNA Damage; DNA, Neoplasm; Endometrial Neoplasms; Endometrium; Female; Genetic Markers; Guanine; Humans; Middle Aged; Optical Imaging; Oxidative Stress

8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most abundant oxidatively modified lesions in DNA and is a marker of the oxidative stress. 8-OHdG is a mutagenic lesion and it can mispair with adenine, causing G:C→T: A transversion. Our task was to determine the 8-OHdG level in patients with colorectal adenocarcinoma directly in tumor tissues and corresponding normal mucosa.. Samples of tumor tissues and corresponding normal mucosa of 47 patients undergoing surgery for colorectal cancer were analyzed. DNA was isolated from both tumor and normal tissues. Then, DNA was hydrolyzed to nucleotides using nuclease P1 and alkaline phosphatase. The 8-OHdG and 2'-dG (2'-deoxyguanosine) were determined in hydrolysates by high-performance liquid chromatography (HPLC) with electrochemical (EC) and UV detector.. The levels of 8-OHdG in colorectal adenocarcinoma tissues were higher than in corresponding normal mucosa. No significant differences were shown in 8-OHdG levels in the cancerous and cancer-free tissues between age and sex and stages A/B and C/D of Duke's classification.. 8-OHdG reflects the local oxidative stress in colon adenocarcinoma tissue together with ageing processes, but not the intensity of tumorigenesis itself. Because of many factors that could influence the oxidative modification of DNA bases, its role as a diagnostic and/or prognostic factor in colon adenocarcinoma seems to be limited.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Deoxyguanosine; DNA; Female; Humans; Male; Oxidative Stress; Poland; Statistics, Nonparametric

Reactive oxygen species-induced oxidative stress in the colon is involved in inflammatory bowel diseases and suggested to be associated with colorectal cancer risk. However, our insight in molecular responses to different oxygen radicals is still fragmentary. Therefore, we studied global gene expression by an extensive time series (0.08, 0.25, 0.5, 1, 2, 4, 8, 16, or 24 h) analyses in human colon cancer (caco-2) cells after exposure to H(2)O(2) or the superoxide anion donor menadione. Differences in gene expression were investigated by hybridization on two-color microarrays against nonexposed time-matched control cells. Next to gene expression, correlations with related phenotypic markers (8-oxodG levels and cell cycle arrest) were investigated. Gene expression analysis resulted in 1404 differentially expressed genes upon H(2)O(2) challenge and 979 genes after menadione treatment. Further analysis of gene expression data revealed how these oxidant responses can be discriminated. Time-dependent coregulated genes immediately showed a pulse-like response to H(2)O(2), while the menadione-induced expression is not restored over 24 h. Pathway analyses demonstrated that H(2)O(2) immediately influences pathways involved in the immune function, while menadione constantly regulated cell cycle-related pathways Altogether, this study offers a novel and detailed insight in the similarities and differences of the time-dependent oxidative stress responses induced by the oxidants H(2)O(2) and menadione and show that these can be discriminated regarding their modulation of particular colon carcinogenesis-related mechanisms.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Antineoplastic Agents; Apoptosis; Caco-2 Cells; Cell Cycle; Colonic Neoplasms; Deoxyguanosine; Electron Spin Resonance Spectroscopy; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Hydrogen Peroxide; Microarray Analysis; Oxidants; Oxidative Stress; Reactive Oxygen Species; Vitamin K 3

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Adenocarcinoma; Aldehydes; Animals; Antibiotics, Antineoplastic; Apoptosis; Caspase 3; Catheter Ablation; Chemotherapy, Adjuvant; Combined Modality Therapy; Deoxyguanosine; DNA Damage; Doxorubicin; Histones; HSP70 Heat-Shock Proteins; Humans; Liver Neoplasms; Mammary Neoplasms, Experimental; Oxidative Stress; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Tyrosine

Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) represents a non-invasive biomarker for oxidative stress and may be useful for monitoring chemotherapeutic and chemopreventive interventions associated with cancer-related alterations in oxidative stress. We describe the development and validation of two separate liquid chromatography/tandem mass spectrometry (LC/MS/MS) selected reaction monitoring (SRM) methods for the determination of 8-oxodG and creatinine in both murine and human urine using stable isotope labelled internal standards. Levels of 8-oxodG were normalised to creatinine. The LC/MS/MS methods were applied to two chemoprevention studies utilising tea polyphenols in humans and TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice. Patients with benign prostatic hyperplasia received 1 g/day of green tea polyphenols (GTP), 1 g/day of black tea theaflavins (BTT) or no treatment for 4 weeks. TRAMP mice received GTP (0.05% in drinking water) for 4 or 25 weeks. Prostate pathology in TRAMP mice was not affected by GTP. Levels of 8-oxodG were not altered by tea polyphenols in either mice or humans. In TRAMP mice, urinary 8-oxodG levels were elevated with increasing age (p < 0.0001) but not changed by the presence of prostate tumours. In conclusion, the LC/MS/MS SRM methods described here are ideally suited for the accurate determination of 8-oxodG and creatinine in urine samples from both clinical and pre-clinical studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Creatinine; Deoxyguanosine; Humans; Male; Mice; Mice, Inbred C57BL; Plant Extracts; Prostatic Neoplasms; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tea; Urinalysis

This study investigated the connection among the oxidative stress, depression and expression of specific genes involved in DNA-damage signaling pathways in patients with colorectal carcinoma (CRC).. A unique Dukes'C subset of patients with newly diagnosed colorectal adenocarcinoma were assessed using the Hamilton Depression Rating Scale (HAMD), Zung Self-rating Depression Scale (SDS), Zung Self-rating Anxiety Scale (SAS), Symptom Checklist 90 (SCL-90) and other multiple-item questionnaires. Oxidative-stress-related parameters in sera and the expression of genes were monitored during a pretreatment period.. Eighty-two eligibility cases were divided into 2 groups based on an HAMD score cutoff of 20: the mean score was 28.29 in Group A (depression, n=52) and 16.50 in Group B (nondepression, n=30). The serum total antioxidant capacity, catalase, and superoxide dismutase concentrations were lower in Group A, whereas those of nitric oxide and malondialdehyde were higher in Group A. Importantly, the 8-hydroxy-deoxyguanosine level was higher in Group A than in Group B (P<.05). Microarray analysis revealed that the expressions of p34, PA26, and ABL were higher in Group A, whereas those of HRAD51, CR6, and XRCC3 were higher in Group B.. Oxidative stress is capable of causing neuronal toxicity via lipid peroxidation, DNA damage, and abnormalities of gene expression, and therefore is a possible pathogenic mechanism underlying depression in patients with CRC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Colorectal Neoplasms; Depressive Disorder; DNA Damage; Female; Gene Expression Regulation, Neoplastic; Guanine; Humans; Male; Middle Aged; Neoplasm Staging; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Personality Inventory; Psychometrics; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Signal Transduction

Recent data from several studies suggest that oxidative stress is involved in the biochemical mechanisms that underlie neuropsychiatric disorders. The present study was designed to investigate oxidative stress status in depressive patients with gastric adenocarcinoma (GA) at TNM stage III. Oxidative stress, depression and expression of specific genes were monitored during a pretreatment period. Serum total antioxidant capacity, catalase, superoxide dismutase concentrations, and antisuperoxide anion capacity (A-ASC) were significantly decreased in depressive patients compared to control subjects, whereas serum malondialdehyde (MDA) levels were significantly increased. Importantly, the formation of 8-hydroxy-deoxyguanosine (8-OHdG) accumulated. Furthermore, SYBR Green real-time PCR revealed that the expression levels of human oxoguanine glycosylase 1 and APEX nuclease 1 (APEX1) were increased in depressive patients. Pearson correlation analysis revealed that depression was positively correlated with SAS, SCL-90, MDA, 8-OHdG and APEX1, but negatively correlated with A-ASC. Thus, this study confirms oxidative imbalance in depressive patients with GA, and oxidative stress may play a role in the onset and exacerbation of depression.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Analysis of Variance; Antioxidants; Catalase; Deoxyguanosine; Depression; DNA Glycosylases; DNA-(Apurinic or Apyrimidinic Site) Lyase; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Stomach Neoplasms; Superoxide Dismutase

Cigarette smoke is strongly associated with NSCLC, but the carcinogenesis of NSCLC is poorly understood.. To discover the role of oxidative stress and anti-oxidative defense in NSCLC, we measured NADPH oxidase (NOX) activity, myeloperoxidase activity, 8-OHdG, and glutathione content from lung specimens. These came from 32 patients: 22 NSCLC patients and ten controls without cancer.. In NSCLC patients, NOX activity was significantly higher both in the malignant (p = 0.001) and non-malignant (p = 0.044) samples from NSCLC patients, than in the control specimens. Myeloperoxidase activity was lower (p = 0.001) and glutathione content (p = 0.009) higher in malignant tissue. No significant difference was observable in 8-OHdG content between patient groups.. Increase in NOX activity in the malignant tissues was independent of smoking history and myeloperoxidase activity, suggesting its independent role in NSCLC pathogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antioxidants; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Case-Control Studies; Deoxyguanosine; Female; Glutathione; Humans; Lung Neoplasms; Male; Middle Aged; NADPH Oxidases; Oxidative Stress; Peroxidase; Smoking; Young Adult

Prolonged exposure to radiation from radionuclei used in medical research can cause DNA damage and mutation, which lead to several diseases including cancer. Radioactivity-based experiments are expensive and associated with specialized training, dedication of instruments, approvals, and cleanup with potential hazardous waste. The objective of this study was to find an alternative to the use of radioactivity in medical research using nucleic acid chemistry. FITC-labeled oligonucleotides that contain wild-type (wt) and modified base (8-oxo-G) at the same position and their complementary unlabeled strand were synthesized. Purified DNA repair enzyme, OGG1, and nuclear lysates from MCF-7 breast cancer cells were incubated with double-stranded FITC-labeled wt and 8-oxo-G oligonucleotide to demonstrate the OGG1 incision assay. We found that FITC-coupled oligonucleotides do not impose a steric hindrance during duplex formation, and the fluorescence intensity of the oligonucleotide is comparable with the intensity of the radioactive oligonucleotide. Moreover, we have seen that the OGG1 incision assay can be performed using these fluorescence oligonucleotides, replacing conventional use of radiolabeled oligonucleotides in the assay. Although the use of fluorescent-labeled oligonucleotides was described in detail for incision assays, the technique can be applied to replace a broad range of experiments, where radioactive oligonucleotides are used, eliminating the hazardous consequences of radiation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Deoxyguanosine; DNA Glycosylases; DNA Repair; Female; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Genes, BRCA1; Humans; Isotope Labeling; Neoplasm Proteins; Nucleic Acid Hybridization; Oligodeoxyribonucleotides; Oligonucleotide Probes; Radioisotopes; Recombinant Fusion Proteins; Substrate Specificity; Transfection; Ubiquitin-Protein Ligases

The inhibitory effects of a novel prodrug, 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid (4'-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 +/- 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 +/- 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 +/- 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Animals; Anticarcinogenic Agents; Azoxymethane; Carcinogens; Chemoprevention; Colitis; Colonic Neoplasms; Coumaric Acids; Deoxyguanosine; Dextran Sulfate; Dipeptides; Disease Models, Animal; Heme Oxygenase (Decyclizing); Intestinal Mucosa; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Prodrugs

Oxidant/antioxidant balance has been suggested as an important factor for initiation and progression of cancer. In order to determine whether the degree of oxidative DNA damage and antioxidant enzyme activities in plasma obtained from patients with gastric and colon cancer who undergo resection can be used as a useful prognostic predictor, plasma level of 8-hydroxydeoxyguanosine (8-OHdG), activities of glutathione peroxidase (G-Px) and superoxide dismutase (SOD) were examined. 19 patients with gastric cancer and 26 patients with colon cancer who were undergoing resection of tumor were included by the study. Venous blood samples were taken just before the surgery. Plasma level of 8-OHdG was determined with ELISA, SOD and G-Px activities in plasma were measured by spectrophotometric kits. 8-OHdG level and activity of G-Px were found to be decreased, SOD activity was found to be increased in both gastric and colon cancer groups as compared to control group. Alpha fetoprotein was found to be correlated with G-Px in the gastric cancer group and correlated with 8-OHdG in the colon cancer group. SOD activity was correlated with CA-15-3 in the gastric cancer group. Low plasma level of 8-OHdG and altered antioxidant activity may implicate the deficient repair of oxidative DNA damage in patients with gastric and colon cancer. Those measured parameters were not found to be related with histopathological data but correlated with some tumor markers.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Aged; alpha-Fetoproteins; Antioxidants; Carcinoma, Adenosquamous; Carcinoma, Signet Ring Cell; Case-Control Studies; Colonic Neoplasms; Deoxyguanosine; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Glutathione Peroxidase; Humans; Lymphoma, B-Cell; Male; Middle Aged; Oxidation-Reduction; Prognosis; Stomach Neoplasms; Superoxide Dismutase

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 DNA damage plays an important role in carcinogens-induced carcinogenesis. 8-hydoxy-2deoxy-guanosine (8-OH-dG), a biomarker of oxidative DNA damage, plays important roles in initiation, progression, and prognosis of lung cancer, and closely relates with mutations of k-ras and p53 genes in carcinogenesis of lung tissue. This study was to detect protein expressions of 8-OH-dG, k-ras, and p53 genes in lung cancer tissues, and to analyze their values in distinguished diagnosis of lung cancer.. Protein levels of 8-OH-dG, k-ras, and p53 in pleural effusion cells from 53 patients with lung cancer, and 53 patients with other benign lung diseases were detected by immunocytochemistry.. Positive rates of 8-OH-dG, k-ras, and p53 protein in cancer group were significantly higher than those in benign disease group [75.5% (40/53) vs. 15.1% (8/53), P < 0.01; 64.2% (34/53) vs. 3.8% (2/53), P < 0.01; and 69.8% (37/53) vs. 18.9% (10/53), P < 0.01; respectively]. Protein levels of 8-OH-dG, k-ras, and p53 protein in cancer group were 1.68+/-1.21, 1.32+/-1.06, and 1.57+/-1.15,respectively. Rank correlation analysis showed that protein expression of 8-OH-dG positively correlated with those of k-ras (RS=0.643, P < 0.01), and p53 (RS=0.827, P < 0.01)u protein expression of k-ras positively correlated with that of p53 (RS=0.897, P < 0.01).. Protein expressions of 8-OH-dG, k-ras, and p53 are up-regulated in pleural effusion cells of lung cancer, and have mutual relations. They may be used as reference markers in diagnosing and screening for lung cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Deoxyguanosine; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, ras; Humans; Lung Neoplasms; Pleural Effusion, Malignant; ras Proteins; Tumor Suppressor Protein p53; Up-Regulation

Lung specimens were collected from 161 non-smoking male patients with carcinoma to determine the deposition of carbon particles and oxidative damage in lung tissues. Morphologically, carbon particles deposited in human lungs with carcinoma were similar to those of diesel exhaust like particles, and mass of particles showed a significant increase with the increasing age of the patients. An increasing age of patient with carcinomas was also associated with 8-oxodeoxy-guanosine (8-oxo-dG) formation, which was analyzed using the HPLC-electrochemical detector method. In addition, it was found that 8-oxo-dG increased in cancerous tissues rather than in non-cancerous ones. To determine whether particles in lung tissues were associated with 8-oxo-dG formation, carbon particles deposited in lung tissues were partially purified by cycling of alkali fusion with 1 M KOH; mutagenic chemicals in particles were extracted and excluded by removal with an equal volume of benzene/methanol and dichloromethane. It was also found that 8-oxo-dG was formed by non-mutagenic particles, and enhanced in the in vivo test using mouse rather than in the in vitro using RAW 254.7 tissue cultured cells. The 8-oxo-dG formation in vivo was due to the fact that hydroxyl radicals might be involved with phagocytosis of non-mutagenic particles in inflammatory cells, and the mutation was induced by hydroxylation of guanine residue on DNA. These results were also demonstrated by the occurrence of alveolar macrophages and neutrophils after intratracheal instillation of particles. These observations suggest that small particles from lung cancer patients further promote oxidative damage when used to treat the mouse lung. Especially, particles from which organic chemicals were removed were highly reactive to oxidative damage and formed 8-oxo-dG.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Animals; Carbon; Cell Line; Child; Deoxyguanosine; Dose-Response Relationship, Drug; Female; Humans; Lung; Lung Neoplasms; Macrophages, Alveolar; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Microscopy, Electron, Scanning; Middle Aged; Monocytes; Particle Size; Pyrenes

This study investigates the genotoxicity and cytotoxicity of oil fumes, formed when peanut oil is heated, on human lung carcinoma pulmonary type II-like epithelium cells. The major mutagenic compound (trans-trans-2,4-decadienal, t-t-2,4-DDE) contained in oil fumes and its effect on the induction of reactive oxygen species (ROS) is also discussed. The results indicate that the methanolic extract of oil fumes can apparently lead to cytotoxicity and oxidative DNA damage. Glutathione (GSH) content, and the activities of antioxidative enzymes such as GSH reductase, GSH peroxidase and GSH S-transferase were adversely reduced by the methanolic extract of oil fumes. t-t-2,4-DDE could produce superoxide anion, hydrogen peroxide and hydroxyl radicals in a phosphate buffer (pH 7.4), and form intracellular ROS, determined by dichlorofluorescein assay in A-549 cells. Moreover, t-t-2,4-DDE caused significant (P <0.05) oxidative damage of the 8-hydroxy-2'-deoxyguanosine formation in A-549 cells at concentrations from 50 to 200 microM. These results demonstrated that the DNA damage in A-549 cells, induced by t-t-2,4-DDE, was related to the ROS formation. The occurrence of t-t-2,4-DDE, therefore, was of significance in the genotoxicity of oxidized oil and fumes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Aldehydes; Cell Line, Tumor; Cell Survival; Comet Assay; Deoxyguanosine; DNA Damage; Dose-Response Relationship, Drug; Hot Temperature; Humans; Lipid Peroxidation; Lung Neoplasms; Mutagens; Oxidative Stress; Plant Oils; Reactive Oxygen Species; Smoke

Unimpaired vitamin D action has been implicated in human cancer prevention. We have previously demonstrated the effectiveness of 1 alpha-dihydroxyvitamin D3 (1,25-D3) to reduce proliferation and increase differentiation in human colon cancer cells. The aim of this study was to investigate, on the one hand, expression of the vitamin D receptor (VDR) and of 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha-hydroxylase) in human normal and malignant colonic tissue and, on the other hand, to determine consequences of reduced or lacking VDR action in a VDR knockout mouse model. In low-grade malignancies of the human colon we found increased VDR and 1 alpha-hydroxylase mRNA expression. However, in late-stage high-grade tumors the vitamin D system is severely compromised. In the mouse colon we found an inverse relationship between VDR levels and proliferation in colon descendens, a tissue known to be specifically affected by nutrients during carcinogenesis. Expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, was significantly augmented with complete loss of VDR. These data suggest that genomic 1,25-D(3) action is necessary to protect against nutrition-linked hyperproliferation and oxidative DNA damage.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Animals; Cell Differentiation; Cell Division; Colon; Colorectal Neoplasms; Deoxyguanosine; Disease Models, Animal; DNA Damage; Humans; Immunohistochemistry; Mice; Mice, Knockout; Oxidative Stress; Receptors, Calcitriol; Reverse Transcriptase Polymerase Chain Reaction

Growth factors can enhance the malignant potential of tumor cells. To examine the relationship between growth factors and tumor progression, we previously established a weakly malignant cell line, ER-1. We found that a 24-hour exposure of ER-1 cells to epidermal growth factor (EGF) induced malignant properties (tumor progression) that were reversible but that, after a 1-month exposure, these changes were irreversible. In this study, we investigated the irreversible changes induced in ER-1 cells by a 1-month exposure to EGF and the possible involvement of oxidative stress.. ER-1 cells were treated with EGF (100 ng/mL) for 1 month in the presence or absence of an antioxidant, N-acetylcysteine or selenium, and compared with untreated control ER-1 cells. We assessed tumor progression by measuring intracellular peroxide levels, 8-hydroxydeoxyguanosine (a marker for oxidative DNA damage) levels, in vitro invasiveness, and in vivo tumorigenicity and metastatic ability. All statistical tests are two-sided.. After ER-1 cells were treated for 1 month with EGF, levels of intracellular peroxide and 8-hydroxyguanosine in the DNA of treated cells were higher than those in the DNA of control cells, and treated ER-1 cells were more tumorigenic and metastatic in vivo and more invasive in vitro than untreated control cells (all P<.001). Levels of 8-hydroxyguanosine in DNA increased as the length of the EGF treatment increased (P<.001). However, when N-acetylcysteine or selenium was added with EGF for 1 month, levels of intracellular peroxide and 8-hydroxyguanosine in DNA were comparable to those in control cells (r =.795). Both tumorigenicity (P =.008) and metastatic ability (P<.001) decreased after addition of N-acetylcysteine or selenium.. The irreversible changes caused by continuous EGF stimulation of ER-1 cells result from increased oxidative damage in the DNA, which generates tumor cells with more malignant characteristics.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetylcysteine; Adenocarcinoma; Animals; Antioxidants; Deoxyguanosine; Disease Progression; DNA Damage; Epidermal Growth Factor; Female; Free Radical Scavengers; Glutathione Peroxidase; Mammary Neoplasms, Experimental; Microscopy, Confocal; Oxidative Stress; Rats; Rats, Inbred SHR; Selenium; Tumor Cells, Cultured

The purpose of this study is to examine the carotenoid effects on lung tumorigenesis induced by intratracheal instillation of diesel exhaust particles (DEP) into mice weekly for 20 wk. It was suggested that active oxygen radicals might play an important role in DEP-induced lung tumorigenesis. Mice were divided to 4 groups of diet containing 0.02% of palm oil carotene, 0.02% of beta-carotene, or no carotenoid with or without DEP. The BF group (4% fat) and the HF group (16% fat) were prepared for each diet group. The experimental period was 12 mo. By the administration of palm oil carotene, neither adenocarcinoma nor adenoma was found in the BF group. In the HF group with palm oil carotene, no adenocarcinoma was observed, and adenoma was reduced. Adenoma in the HF group was not greatly reduced by beta-carotene, but rather increased in the BF group. No adenocarcinoma was found in either the BF or the HF groups with beta-carotene. The 8-hydroxydeoxyguanosine/deoxyguanosine ratio in palm carotene groups was lower than in the other groups, while that in beta-carotene groups was not. From these results, palm oil carotene was suggested to prevent lung tumorigenesis by its protective effect on DNA from active oxygen. Beta-carotene was supposed to have different effects from palm oil carotene on lung tumorigenesis. Besides the chemopreventive effect, the growth of mice was inhibited by the administration of palm oil carotene. Further studies are necessary to elucidate the mechanisms of carotenoid effects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adenoma; Animals; Antioxidants; beta Carotene; Carotenoids; Deoxyguanosine; Dietary Fats; DNA Damage; Growth; Lung; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Reactive Oxygen Species; Time Factors; Vehicle Emissions; Vitamins

Human prostate tissues are vulnerable to oxidative DNA damage. The risk of prostate cancer is lower in men reporting higher consumption of tomato products, which contain high levels of the antioxidant lycopene. We examined the effects of consumption of tomato sauce-based pasta dishes on lycopene uptake, oxidative DNA damage, and prostate-specific antigen (PSA) levels in patients already diagnosed with prostate cancer.. Thirty-two patients with localized prostate adenocarcinoma consumed tomato sauce-based pasta dishes for the 3 weeks (30 mg of lycopene per day) preceding their scheduled radical prostatectomy. Serum and prostate lycopene concentrations, serum PSA levels, and leukocyte DNA oxidative damage (ratio of 8-hydroxy-2'-deoxyguanosine [8-OHdG] to 2'-deoxyguanosine [dG]) were assessed before and after the dietary intervention. DNA oxidative damage was assessed in resected prostate tissue from study participants and from seven randomly selected prostate cancer patients. All statistical tests were two-sided.. After the dietary intervention, serum and prostate lycopene concentrations were statistically significantly increased, from 638 nM (95% confidence interval [CI] = 512 to 764 nM) to 1258 nM (95% CI = 1061 to 1455 nM) (P<.001) and from 0.28 nmol/g (95% CI = 0.18 to 0.37 nmol/g) to 0.82 nmol/g (95% CI = 0.57 to 1.11 nmol/g) (P <.001), respectively. Compared with preintervention levels, leukocyte oxidative DNA damage was statistically significantly reduced after the intervention, from 0.61 8-OHdG/10(5) dG (95% CI = 0.45 to 0.77 8-OHdG/10(5) dG) to 0.48 8-OHdG/ 10(5) dG (95% CI = 0.41 to 0.56 8-OHdG/10(5) dG) (P =.005). Furthermore, prostate tissue oxidative DNA damage was also statistically significantly lower in men who had the intervention (0.76 8-OHdG/10(5) dG [95% CI = 0.55 to 0.96 8-OHdG/10(5) dG]) than in the randomly selected patients (1.06 8-OHdG/10(5) dG [95% CI = 0.62 to 1.51 8-OHdG/10(5) dG]; P =.03). Serum PSA levels decreased after the intervention, from 10.9 ng/mL (95% CI = 8.7 to 13.2 ng/mL) to 8.7 ng/mL (95% CI = 6.8 to 10.6 ng/mL) (P<.001).. These data indicate a possible role for a tomato sauce constituent, possibly lycopene, in the treatment of prostate cancer and warrant further testing with a larger sample of patients, including a control group.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Age Factors; Aged; Carotenoids; Chromatography, High Pressure Liquid; Deoxyguanosine; Diet Therapy; DNA; DNA Damage; Electrochemistry; Humans; Leukocytes; Lycopene; Male; Middle Aged; Oxidative Stress; Oxygen; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Solanum lycopersicum; Time Factors

This study was done to discover the underlying mechanism of the inhibitory effect of sericin against colon tumorigenesis. Mice were fed a diet with 30 g/kg sericin for 115 d, and given a weekly injection of 1,2-dimethylhydrazine (10 mg/kg body weight) for the initial 10 wk. Dietary supplemental sericin caused a 62% reduction in the incidence of colonic adenoma (P<0.05), but did not affect the incidence of colonic adenocarcinoma. Sericin intake significantly reduced the number of colon adenomas. Consumption of sericin significantly reduced the BrdU labeling index of colonic proliferating cells and the expression of colonic c-myc and c-fos. The levels of colonic 8-hydroxydeoxyguanosine, 4-hydroxynonenal, and inducible nitric oxide synthase protein were significantly suppressed by sericin. The results suggest that dietary sericin suppresses the development of colon tumors by reducing oxidative stress, cell proliferation, and nitric oxide production.

Topics: 1,2-Dimethylhydrazine; 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adenoma; Aldehydes; Animals; Apoptosis; Carcinogens; Cell Division; Colonic Neoplasms; Deoxyguanosine; Immunohistochemistry; Intestinal Mucosa; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Peptides, Cyclic; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Sericins

This study examined the effects of lyophilized black raspberries (BRB) on azoxymethane (AOM)-induced aberrant crypt foci (ACF), colon tumors, and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in male Fischer 344 rats. AOM was injected (15 mg/kg body wt i.p.) once per week for 2 wk. At 24 h after the final injection, AOM-treated rats began consuming diets containing 0%, 2.5%, 5%, or 10% (wt/wt) BRB. Vehicle controls received 5% BRB or diet only. Rats were sacrificed after 9 and 33 wk of BRB feeding for ACF enumeration and tumor analysis. ACF multiplicity decreased 36%, 24%, and 21% (P < 0.01 for all groups) in the 2.5%, 5%, and 10% BRB groups, respectively, relative to the AOM-only group. Total tumor multiplicity declined 42%, 45%, and 71% (P < 0.05 for all groups). Although not significant, a decrease in tumor burden (28%, 42%, and 75%) was observed in all BRB groups. Adenocarcinoma multiplicity decreased 28%, 35%, and 80% (P < 0.01) in the same treatment groups. Urinary 8-OHdG levels were reduced by 73%, 81%, and 83% (P < 0.01 for all groups). These results indicate that BRB inhibit several measures of AOM-induced colon carcinogenesis and modulate an important marker of oxidative stress in the Fischer 344 rat.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adenoma; Animals; Anthocyanins; Anticarcinogenic Agents; Azoxymethane; Calcium; Cholesterol; Colonic Neoplasms; Coumaric Acids; Deoxyguanosine; Diet; Ellagic Acid; Freeze Drying; Fruit; Oxidative Stress; Rats; Rats, Inbred F344; Rosaceae; Sitosterols

Polymorphic genes for the peroxide scavenger glutathione peroxidase I (GPX1) and 8-hydroxydeoxyguanosine (8-OHdG) DNA glycosylase/apurinic (AP) lyase (hOGG1) map to loci on chromosome 3p which are subject to frequent loss of heterozygosity (LOH) in lung tumours. Levels of the pro-mutagenic, oxidative DNA lesion 8-OHdG, were measured in 37 paired normal and tumorous lung specimens using HPLC with electrochemical detection. Lung tumours were also analysed for 3p LOH by fluorescent PCR with Genescan analysis. No significant difference was observed between 8-OHdG levels in tumour [7.7 +/- 6.7 (mean +/- SE) 8-OHdG/10(6) 2'-deoxyguanosine (dG)] and normal (8.1 +/- 8.8 8-OHdG/10(6) dG) lung tissue. Adduct levels in normal lung tissue DNA were not associated with constitutive hOGG1 genotype although there was a trend towards lower 8-OHdG levels in individuals possessing the ALA6 GPX1 polymorphism. Lung tumours exhibiting 3p LOH (40%) contained higher levels of 8-OHdG adducts (10.9 +/- 2.6 8-OHdG/10(6) dG) (P = 0.05) and lower GPX1 enzyme activity [45.5 nmol glutathione (GSH)/min/mg] (P = 0.09) when compared with tumours without LOH at these sites (5.55 +/- 0.87 8-OHdG/10(6) dG and 63.6 nmol GSH/min/mg, respectively). In conclusion, tumours with 3p LOH at loci associated with hOGG1 and GPX1 appear to have compromised oxidative defence mechanisms as measured by reduced GPX1 enzyme activity and elevated 8-OHdG levels and this may affect the prognosis of lung cancer patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Amino Acid Substitution; Carcinoma, Squamous Cell; Chromosomes, Human, Pair 3; Deoxyguanosine; DNA Adducts; DNA-Formamidopyrimidine Glycosylase; DNA, Neoplasm; Female; Genotype; Glutathione Peroxidase; Humans; Isoenzymes; Loss of Heterozygosity; Lung Neoplasms; Male; N-Glycosyl Hydrolases; Neoplasm Proteins; Oxidative Stress; Polymorphism, Genetic; Smoking

p-Dichlorobenzene (pDCB) is a male rat kidney carcinogen believed to act through alpha2u-globulin nephropathy. Recent data on metabolism, however, suggest a potential for generating oxidative stress. To examine possible mechanisms of kidney carcinogenesis, pDCB was studied for ability to produce 8-oxodeoxyguanosine (8-oxodG) in kidney nuclear DNA and for initiating activity in a two-stage renal carcinogenesis model. F344 male rats were given pDCB by intragastric instillation, 5 days/week for 13 weeks at 300 mg/kg per day, which is a carcinogenic dose with chronic administration. To assess initiation after exposure, trisodium nitrilotriacetic acid (NTA), a kidney tumor promoter was given in the drinking water at 1,000 ppm for 39 weeks. At the end of the exposure segment, pDCB did not produce an increase of 8-oxodG levels in the kidney nuclear DNA in contrast to potassium bromate (KBrO3). Following NTA promotion, no neoplastic lesions occurred in rats given pDCB, although diethylnitrosamine carcinogenesis was enhanced. Thus, pDCB did not produce oxidative DNA damage in the rat kidney or effect initiation of kidney carcinogenesis. These data suggest that oxidative stress is not involved in pDCB-induced renal carcinogenesis. The alpha2u-globulin-mediated chronic nephropathy probably acts as a promoter, not an initiation of renal carcinogenesis. Accordingly, pDCB is assessed to have no cancer hazard to humans who are not susceptible to the alpha2u-globulin nephropathy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Animals; Body Weight; Carcinogens; Cell Division; Cell Nucleus; Chlorobenzenes; Cystadenoma; Deoxyguanosine; DNA Damage; DNA, Neoplasm; Hyperplasia; Immunohistochemistry; Kidney Neoplasms; Male; Organ Size; Oxidation-Reduction; Rats; Rats, Inbred F344

The risk for prostate cancer seems to be reduced by certain antioxidant compounds (vitamins E and A, and selenium).. Antioxidant enzymes and oxidative damage products were localized in normal prostatic epithelium and malignant glands in primary and metastatic prostatic adenocarcinomas, using well-characterized antibodies and immunoperoxidase techniques.. Antioxidant enzymes and four markers of oxidative damage were compared in basal and secretory cells of normal prostatic epithelium and prostate adenocarcinoma cells, and each cell type had unique patterns of enzymes and oxidative damage products. One marker of oxidative damage, a fluorophore derived from 4-hydroxy-2-nonenal-lysine adduction, was found in secretory cells of normal but not malignant epithelium, demonstrating a different oxidative metabolism in normal vs. malignant prostate epithelium. Metastatic lesions from primary prostate cancer had higher levels of manganese superoxide dismutase and nuclear oxidative damage products than did primary tumors.. Antioxidant enzymes and oxidative damage products are modulated in metastatic compared to primary prostate cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Antibodies, Monoclonal; Antioxidants; Bone Neoplasms; Catalase; Deoxyguanosine; Glutathione Peroxidase; Humans; Immunoenzyme Techniques; Lipofuscin; Male; Prostate; Prostatic Neoplasms; Reactive Oxygen Species; Superoxide Dismutase; Tyrosine

Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3-nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adenoma; Adult; Aged; Aldehydes; Case-Control Studies; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Deoxyguanosine; Epithelial Cells; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nitrates; Oxidants; Oxidative Stress; Reactive Oxygen Species; Time Factors

BPDE-I-DNA and oxidative DNA adducts (8-OHdG) were investigated in stomach tissues (tumor and tumor-adjacent) of patients (N = 211) with gastric adenocarcinoma and in normal stomach tissues (N = 113). In each stomach specimen, the levels of BPDE-I-DNA adducts were quantitatively measured by enzyme linked immunosorbent assay (ELISA) and oxidative DNA damage was measured by HPLC-ECD. Higher levels of total BPDE-I-DNA adduct were observed in tumor (4.20 +/- 0.59 fmol/microg DNA) and tumor-adjacent (3.68 +/- 0.62 fmol/microg DNA) tissues than in normal stomach tissues (2.80 +/- 0.53 fmol/microg DNA) but were not significant. In males, BPDE-I-DNA adduct was significantly higher in tumor tissues (4.25 +/- 0.42 fmol/microg DNA) than in normal tissues (2.83 +/- 0.59 fmol/microg DNA) (P < 0.05). In smokers, BPDE-I-DNA adduct was slightly higher in tumor tissues (4.92 +/- 0.82 fmol/microg DNA) than in tumor-adjacent tissues (3.99 +/- 0.92 fmol/microg DNA). Gastric cancer patients had significantly higher levels of 8-OHdG in their tumor-adjacent (7.54 +/- 0.43 residues/10(5) dG) and tumor tissues (6.29 +/- 0.39 residues/10(5) dG) than in normal tissues (2.86 +/- 0.11 residues/10(5) dG) (P < 0.001). Smokers showed higher levels of 8-OHdG in both tumor (6.44 +/- 0.62 residues/10(5) dG) and tumor-adjacent (8.12 +/- 0.68 residues/10(5) dG) tissues than in non-smokers (5.80 +/- 0.47 and 7.11 +/- 0.57 residues/10(5) dG, respectively). 8-OHdG levels were significantly increased in positive tissues with Helicobacter pylori (H. pylori) infection compared with negative tissues (P < 0.01). Also, the frequency of H. pylori infection was higher in tumor-adjacent tissues (73%) than in tumor (42%) or normal tissues (44%). These results demonstrate that there are higher levels of 8-OHdG and BPDE-I-DNA adducts in tumor and tumor-adjacent tissues than in normal tissues and that these higher levels might be related to gastric tumorigenesis, although benzo[a]pyrene could be a minor contributing component in the environment.

Topics: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Deoxyguanosine; DNA Adducts; DNA Damage; Female; Humans; Male; Middle Aged; Stomach Neoplasms

Deletions of loci on chromosomes 5q, 17p, 18q, and 22q, together with the incidence of p53 mutations and amplification of the double minute-2 gene were investigated in the sporadic colorectal tumors of 44 patients from a Spanish community. Chromosome deletions were analyzed by means of loss of heterozygosity analysis using a restriction fragment length polymorphism assay. Allelic losses were also detected by polymerase chain reaction (PCR)-single-stranded conformation polymorphism (SSCP) analysis of a polymorphic site in intron 2 of the p53 gene. The percentages of genetic deletions on the screened chromosomes were 39.3% (5q), 58.3% (17p), 40.9% (18q), and 40% (22q). Mutations in p53 exons 2-9 were examined by PCR-SSCP analysis and direct sequencing of the mutated region. Twenty of 44 tumor samples (45.45%) showed mutations at various exons except for exons 2, 3, and 9, the most frequent changes being G-->T transversion and C-->T transition. Because oxygen-free radicals play a role in the carcinogenesis process, we evaluated the oxidative status of the colorectal tumors. Antioxidant activities, lipid peroxidation, and DNA-damaged product concentrations in colon tumors and normal mucosa were compared. In tumor tissues, superoxide dismutase and catalase decreased fourfold and twofold, respectively, whereas glutathione peroxidase and reduced glutathione increased threefold. Malondialdehyde and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were twofold higher in colorectal tumors than in normal mucosa. Seven of 10 DNA tumor samples (70%) showing higher values of 8-OHdG also had genetic alterations at different chromosomal loci. In these samples, the p53 gene was deleted or mutated in 71.4% of cases. We concluded that the observed changes in the oxidative metabolism of the tumor cells and the consecutive increase in DNA damage may potentiate the genomic instability of different chromosomal regions, leading to further cell malignancy and tumor expansion.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Adult; Aged; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 18; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 5; Colorectal Neoplasms; Deoxyguanosine; DNA Mutational Analysis; DNA, Neoplasm; Female; Gene Amplification; Genes, p53; Genetic Markers; Glutathione; Heterozygote; Humans; Lipid Peroxides; Male; Middle Aged; Nuclear Proteins; Oxidation-Reduction; Polymorphism, Single-Stranded Conformational; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Sequence Deletion; Spain